CN118973569A - 5-Methoxy-N,N-dimethyltryptamine for the treatment of bipolar disorder - Google Patents

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof is used to treat a patient diagnosed with bipolar disorder.

Description

5-Methoxy-N,N-dimethyltryptamine for the treatment of bipolar disorder

Technical Field

The present invention relates to an improved method for treating bipolar disorder (BD), comprising administering a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof to a patient in need thereof. The treatment improves not only depressive mood, but also particularly improves characteristic aspects of BD, such as sleep disturbance, psychomotor retardation (reduced energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social/emotional withdrawal or alienation (anhedonia, emotional withdrawal, and emotional apathy).

The treatment also counteracted suicidal ideation. In addition, the treatment also improved mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation).

Treatment according to the invention reduces or eliminates the risk of treatment-induced mania or hypomania.

Background Art

Bipolar disorder is a mental health condition characterized by dramatic mood swings, including low moods (major depressive episodes) and high moods (manic or hypomanic episodes). Bipolar disorder is a relapsing, chronic disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

Symptoms that indicate a depressive episode include depressed mood, such as feeling sad, empty, hopeless, or tearful; marked loss of interest or pleasure in all or almost all activities; significant weight loss, weight gain, or decreased or increased appetite when not dieting; insomnia or excessive sleeping; restlessness or sluggish behavior; fatigue or low energy; feelings of worthlessness or excessive or inappropriate guilt; decreased ability to think or concentrate, or indecisiveness; and thinking about, planning, or attempting suicide.

A major depressive episode typically includes five or more of these symptoms. It includes symptoms severe enough to cause significant difficulty in daily situations, such as work, school, social activities, or relationships.

During a manic or hypomanic episode, people appear or feel unusually energetic, happy, or irritable, and they often make impulsive decisions with little thought to the consequences. The need for sleep is also usually decreased.

If the elevated mood is severe or accompanied by psychosis, it is called mania; if it is less severe, it is called hypomania. Hypomania does not involve psychotic symptoms.

In bipolar disorder, periods of depression and periods of elevated mood can each last from a few days to a few weeks. Episodes of mood swings can occur infrequently or many times a year.

Bipolar disorder was previously known as manic-depressive illness. However, it has long been recognized that this disorder is different from major depressive disorder. DSM-III (Diagnostic and Statistical Manual of Mental Disorders III; 1980) first formally separated bipolar disorder (BD) with mania from non-bipolar major depressive disorder (MDD).

If at least one manic episode occurs (with or without a depressive episode), BD is classified as bipolar I. If at least one hypomanic episode (but not a full manic episode) and one major depressive episode occur, it is classified as bipolar II. If these symptoms are caused by medications or medical problems, the symptoms are not diagnosed as bipolar disorder.

Hypomania is a milder form of mania, and bipolar II disorder is not a milder form of bipolar I. A 13.6-year study on the natural course of bipolar II disorder found that patients were symptomatic during 53.9% of the follow-up weeks, with depressive symptoms occurring during 50.3% of the follow-up weeks (Judd, L., Akiskal, H., Schettler, P., Coryell, W., Endicott, J., Maser, J., Solomon, D., Leon, A., and Keller, M., 2003. A Prospective Investigation of the Natural History of the Long-term Weekly Symptomatic Status of Bipolar II Disorder. Archives of General Psychiatry, 60(3), p. 261). A similar study of patients with bipolar I disorder found that patients were symptomatic during 47.3% of the follow-up weeks, with depressive symptoms accounting for 31.9% of the follow-up weeks (Judd, L, Akiskal, H., Schettler, P., Endicott, J., Maser, J., Solomon, D., Leon, A., Rice, J., and Keller, M., 2002. The Long-term Natural History of the Weekly Symptomatic Status of Bipolar I Disorder. Archives of General Psychiatry, 59(6), p. 530). It is therefore clear that depressive symptoms dominate the symptomatic state of both types of bipolar disorder - most prominently in bipolar II disorder. Evidence suggests that a greater proportion of patients with bipolar II disorder attempt suicide (Karanti, A., Kardell, M., Joas, E., Runeson, B., E. and Landén, M., 2019. Characteristics of bipolar I and II disorders: A study of 8766individuals. Bipolar Disorders, 22(4), pp. 392-400).

In most cases, bipolar disorder is treated with medication and psychological counseling (psychotherapy). However, current treatments have had only limited success, for example, due to often limited or unsustainable treatment responses, late onset of responses, side effects that limit long-term medication administration, and inconvenient dosing regimens that often limit patient compliance.

The evidence for or against the use of antidepressants in patients with BD remains highly inconsistent (Baldessarini 2020) and a recent national study found that 54.9% of patients with bipolar II disorder were receiving antidepressant medication (Karanti, Kardell et al. 2020). This is despite the fact that several reports have shown that patients with BD may experience clinical worsening when treated with antidepressants, exhibiting symptoms such as agitation, insomnia, anger and irritability, and are at increased risk of suicidal behavior (Baldessarini 2020). Treatment-induced mania or hypomania (TEM) is a significant risk associated with such treatment.

Although there are many treatment options available for BD in addition to antidepressants, many of them are associated with adverse reactions. Quetiapine, approved for acute treatment of depressive episodes in bipolar I and II, is associated with weight gain, dry mouth, sedation, somnolence, and dizziness-leading to a high rate of discontinuation due to adverse reactions in patients receiving quetiapine in placebo-controlled trials (Calabrese, Keck et al. 2005, Thase, Macfadden et al. 2006, Suppes, Datto et al. 2010). In addition, quetiapine is usually titrated over a period of time spanning multiple days, resulting in delayed onset. Studies have shown that lurasidone leads to a higher incidence of nausea and extrapyramidal events compared with placebo (Loebel, Cucchiaro et al. 2014, Loebel, Cucchiaro et al. 2014). Furthermore, olanzapine and the olanzapine-fluoxetine combination can cause somnolence and weight gain (Tohen, Vieta et al. 2003).

Even in treated BD, depression as the primary psychopathology is associated not only with excess morbidity but also with mortality due to co-occurring general medical disorders. The risk of medical disorders including diabetes or metabolic syndrome and cardiovascular disorders and the associated mortality are several times higher than in the general population or in patients with other psychiatric disorders.

Furthermore, the normalized suicide mortality rate in BD is 20 times higher than the general population mortality rate and exceeds the mortality rate of other major psychiatric disorders.

The current state of BD treatment efficacy is aptly summarized by Baldessarini et al:

“All available pharmacological treatments for bipolar depression have limited efficacy and carry the risk of adverse metabolic or neurologic effects.”

Therefore, new treatments for BD represent a significant unmet medical need.

While there has been a recent surge of interest in the use of hallucinogens to treat psychiatric disorders, this has not led to treatments for BD to date. This is due to a general lack of clinical data to allow conclusions to be drawn about the clinical utility of hallucinogens in BD, and also because of particular concerns that hallucinogens may actually worsen the illness, particularly by inducing mania or hypomania.

Hallucinogens, including LSD, are chemical compounds, some naturally occurring and some synthetic, that are defined by their ability to induce distortions of the senses, such as changes in auditory and visual perception, as well as distortions of mood and cognition, after ingestion. The term hallucinogen covers a fairly broad group of psychoactive molecules with different modes of action. Some psychiatric disorders have been proposed to be treatable in principle with psychoactive molecules, such as LSD.

However, no psychedelic drug has yet to be approved by any regulatory agency. In fact, clinical experience with such molecules is still quite limited.

One compound that has been studied in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO 2020/169850 reports on tests in healthy volunteers and a clinical trial involving patients with treatment-resistant depression (TRD), a form of major depressive disorder.

In this context, it is an object of the present invention in particular to provide a therapy that is more effective than previously described therapies (i.e., a) a greater percentage of patients experience a clinical response, b) a greater mean clinical response, c) a clinical response occurs earlier, and/or d) a clinical response is more durable).

It is a further object of the present invention to provide compounds for improved psychoactive therapy and dosing regimens for said therapy, said therapy having better safety and/or better tolerability than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapy and dosing regimens for said therapy, said therapy being more convenient than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapy and dosing regimens for said therapy, said therapy being associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. It is a still further object of the present invention to identify specific disease aspects and subgroups of specific disease aspects that may benefit from such improved psychoactive therapies.

Summary of the invention

The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating patients diagnosed with bipolar disorder.

Patients may be diagnosed as having bipolar II disorder or as having bipolar I disorder. Patients treated will typically be suffering from a current major depressive episode. Patients may have been treated previously without success.

5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

Administration is preferably performed by inhalation. For this purpose, an aerosol containing (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof can be used, wherein the aerosol has an aerosol particle mass density of about 0.5 mg/l to about 18 mg/l.

Treatment success can be assessed using a variety of rating scales, including but not limited to the Bipolar Depression Rating Scale (BDRS), the Montgomery-Asberg ) Depression Rating Scale (MADRS) and Clinical Global Impression-Severity Scale (CGI-S). Treatment brings about multiple therapeutic effects.

A clinical response (reflected, for example, by a decrease in Clinical Global Impression-Severity (CGI-S) score) generally occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A clinical response is observed on day 1, for example, after about 24 hours.

For the treatment of sleep disorders, a clinical response (reflected, for example, by a decrease in CGI-S score) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Patients did not experience treatment-induced mania or hypomania.

Treatment specifically results in improvement in at least one of sleep disturbance, psychomotor retardation, negative thinking, anxiety, cognitive dysfunction, and social/emotional withdrawal or alienation.

In addition, treatment reduces or eliminates suicidal thoughts.

It also reduces or eliminates at least one of the psychotic symptoms; irritability; instability; increased motor drive; increased speech; and agitation.

DETAILED DESCRIPTION

definition

As used in the context of the present invention, unless otherwise indicated, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, wherein the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered may be calculated based on the weight of the free base, assuming the use of equimolar amounts.

As used in the context of the present invention, a "patient" to be treated is a human subject who has been diagnosed by a licensed professional as suffering from a bipolar disorder, such as bipolar disorder type II, in accordance with generally accepted medical practice. For example, the diagnosis may be made in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association. The diagnosis will be made by a physician or psychologist. It is not sufficient for the human subject to believe that he or she suffers from the disorder.

As used in the context of the present invention, "suicidal ideation" means thinking about, considering, or planning to commit suicide. A doctor or psychologist will diagnose a patient for the presence of suicidal ideation using established protocols and methods for diagnosing suicidality. Generally, it is not enough for a patient to believe that they suffer from suicidal ideation. In some cases, a patient with suicidal ideation will be at risk for imminent suicide, or will be considered to have "suicidal intent."

As used in the context of the present invention, unless otherwise indicated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, illness or disorder, and includes the administration of the compounds and methods according to the present invention to alleviate the signs and/or symptoms of the disease or to eliminate the disease, illness or disorder.

As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human being that is being sought by a researcher, physician or other clinician, including alleviation of the signs and/or symptoms of the disease, condition or disorder being treated.

"Clinical response" includes, but is not limited to, improvements on rating scales. These scales assess various disease aspects. Scales that can be used according to the present invention include the Brief Psychiatric Rating Scale (BPRS), the Bipolar Depression Rating Scale (BDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the 17-item Hamilton Depression Rating Scale (HAM-D). Other related scales for assessing clinical outcomes include the Young's Mania Rating Scale (YMRS), the Clinically Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Columbia Suicide Severity Rating Scale (C-SSRS).

Clinical response can also be assessed based on the Clinical Global Impression-Severity scale (CGI-S), the Patient Global Impression-Severity scale (PGI-S), the Clinical Global Impression-Improvement scale (CGI-I), or the Patient Global Impression-Improvement scale (PGI-I).

Individual items of the scales indicated as well as subcombinations of individual items can be used to assess specific disease aspects.

When clinical response is assessed at an early time point after drug administration (e.g., 2 hours), such endpoints can be reasonably modified based on endpoints developed for longer recall periods (e.g., MADRS is typically 7 days) (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration). This also applies to the BDRS (particularly the sleep disturbance items) and any other scale used in this article, unless a recall period is specifically specified.

The considerations outlined apply to early time points because, on the one hand, in order to assess clinical response, the influence of the patient's pre-treatment status on any scores recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

At a later time point, such as on day 1 or later, all items of the relevant scales used to assess clinical response can generally be assessed, using an appropriate recall period (if necessary), so that no pre-treatment scores need to be carried forward.

The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a 19-question self-rating questionnaire that asks respondents to indicate how often they have experienced certain sleep difficulties in the past month or another appropriate recall window.

Nineteen self-rated questions assess multiple factors related to sleep quality, including estimates of sleep duration and latency and estimates of the frequency and severity of specific sleep-related problems. The 19 items are divided into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping pills; and (7) daytime dysfunction.

Each component is scored from 0 to 3. Higher scores indicate more severe sleep disturbance. A detailed scoring description of the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May; 28(2): 193-213.

The seven component scores are then summed to create an overall score ranging from 0-21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A total score cutoff of 5 distinguishes those with poor sleep quality from those with good sleep quality. A total score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or less.

The Verbal Recognition Memory (VRM) test assesses verbal memory and new learning. It measures the ability to encode and subsequently retrieve verbal information. During this task, 18 words are displayed on the screen and participants are subsequently asked to recall these words in a free recall phase. This is followed by a recognition test, in which participants are presented with 36 words (including target words and distractors) and asked to answer "yes" or "no" as to whether they have seen the word before. After a 20-minute delay period, another recognition test follows, this time using a new set of distractor words. Administration time is approximately 6 minutes (including immediate and delayed recall).

The rapid visual processing (RVP) test is a sensitive tool for assessing sustained attention. A white box is displayed in the center of the screen, within which single numbers from 2 to 9 appear in a pseudo-random order at a rate of 100 numbers per minute on the screen. The patient must detect a series of target sequences (e.g., 3-5-7, 2-4-6, and 4-6-8) and touch a button when the last number of the target sequence is seen. Nine target sequences appear at 100 numbers per minute. The task duration is approximately 7 minutes.

Spatial working memory (SWM) tasks require the retention and manipulation of visual-spatial information. This self-ordered test provides a measure of strategy as well as working memory errors. The test involves multiple colored squares (boxes) displayed on a screen, which requires the selection of strategies to fill in the empty columns. The test takes about 4 minutes to complete. Outcome measures of SWM include errors and strategies. The computerized Corsi Block will be the version of the SWM task used in this study.

The digit symbol substitution task (DSST) is a version of the original paper-pencil task taken from the Wechsler Adult Intelligence Scale (Royer, F.L and Janowitch, L, 1973. Performance of process and reactive schizophrenics on a symbol-digit substitution task. Percept Mot Skills 37(1): 63-70). The patient is presented with a coding scheme consisting of a row of squares at the top of the screen, in which nine digits are randomly associated with specific symbols. The same symbols are displayed at the bottom of the screen in a fixed order as a row of individual response buttons. The randomization process is chosen so that the symbols never appear in the same ordinal position within two rows. The coding scheme and response buttons remain visible while the patient is presented with a series of single digits appearing in succession in the center of the screen. The task is to match each digit with a symbol from the coding list and then click the corresponding response button. The number of correctly coded digits within 3 minutes is the performance measure.

Treatment outcomes are assessed by using one or more indices or scales at one or more time points after completion of the course of treatment.

The assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is about 2 to 3 hours after the last administration. The assessment can be performed, for example, about 2 hours or about 3 hours after the last administration.

If more than one index or scale is administered, it cannot be done simultaneously. Thus, while one index or scale may be administered about 2 hours after the last administration of 5-MeO-DMT, another index or scale may be administered, for example, about 3 hours after the last administration of 5-MeO-DMT. It is contemplated herein that assessments performed at two time points, or generally within a time frame of about 2 to 3 hours, are equally reflective of early treatment outcomes.

Evaluation on day 1 or day 1 means evaluation on the second day after administration. Evaluation will be performed no earlier than 12 hours after the last administration, and in any case no earlier than one night after the last administration, and no later than 36 hours after the last administration. Evaluation can be performed after about 24 hours.

Assessment on or at day 7 means assessment performed on the seventh day after administration (the day of administration is day 0). Similar definitions apply to other assessment times measured in days.

As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "application") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient's body via any route. Preferably, the active compound is administered by inhalation, nasal, buccal or sublingual administration.

As used in the context of the present invention, unless otherwise indicated, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined order of one or more separate administrations.

As used herein, "aerosol" means a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and tiny suspended solid and/or liquid particles. The term "degradation product" refers to a compound produced by the chemical modification of 5-MeO-DMT due to a chemical reaction during the formation of the aerosol. Such reactions include, but are not limited to, oxidation. When describing the percentage of "degradation product" in the context of the present invention, this refers to the amount of 5-MeO-DMT degradation products present in the sample divided by the amount of 5-MeO-DMT plus 5-MeO-DMT degradation products present in the sample multiplied by 100%, that is, (the sum of the amounts of all 5-MeO-DMT degradation products present in the sample)/((the amount of 5-MeO-DMT present in the sample)+(the sum of the amounts of all 5-MeO-DMT degradation products present in the sample)) x 100%. As used herein, the term "impurity" refers to an unwanted compound that contaminates a sample of 5-MeO-DMT (or a pharmaceutically acceptable salt thereof). Impurities may be included in the starting materials prior to aerosol formation or may be degradation products.

The term "purity" refers to 100% minus the percentage of all 5-MeO-DMT degradation products present and all other impurities present, i.e., 100% - (the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) / (the amount of 5-MeO-DMT present + the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) x 100%.

The term "mass median aerodynamic diameter" (MMAD) is the diameter at which 50% of the particles present in the aerosol are larger than the calculated diameter and 50% of the particles are smaller than the calculated diameter. The term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle formation rate" refers to the mass of 5-MeO-DMT aerosolized per unit aerosolization time.

Bipolar disorder

Bipolar disorder is characterized by a variety of symptoms and has various facets.

The primary psychopathology is depression, and the presentation of a patient going through a depressive phase may initially lead to the patient being diagnosed as suffering from major depressive disorder (MDD). However, even during the depressive phase, BD has a variety of features that define it as distinct from the former.

Of particular interest here are the symptoms that are more strongly associated with BD than with other psychiatric disorders, as these are indicators of how patients are evaluated for treatment. Although many symptoms can be said to span multiple disorders, considerable work has been done to identify several symptoms that are strongly present in patients with BD: sleep disturbances, psychomotor retardation (decreased energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social/emotional withdrawal or detachment (anhedonia, emotional withdrawal, and emotional flattening). Characteristic symptoms also include suicidal ideation. In addition, characteristic symptoms include mixed symptoms (psychotic symptoms; irritability; instability; increased motor drive; increased verbalization; agitation).

Clinical assessment tools for BD, such as the Bipolar Depression Rating Scale (BDRS), have been developed and validated that take these symptoms into account.

The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. BDRS can be used for clinical use after trained assessors verify. According to clinical interviews, the BDRS project assesses the severity of depression and/or mixed symptoms that the patient currently and in the past few days have shown. If the current symptoms are inconsistent with the symptoms of the past few days, the assessment should reflect the current symptoms. The scale contains 20 questions and the highest score is 60. The higher the score, the greater the severity.

Questions concern depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; emotional flattening; feelings of worthlessness; helplessness and hopelessness; suicidal ideation; guilt; psychotic symptoms; irritability; lability; increased drive to move; increased verbalization; and agitation.

Each of these aspects was evaluated and assigned a score of 0, 1, 2, or 3.

Depressed mood was scored as 0 if there was no self-reported and/or observed depression, as evidenced by feelings of gloom, sadness, pessimism, hopelessness, and helplessness; 1 (mild) if there were brief or transient periods of depression, or mild depressed mood; 2 (moderate) if depressed mood was evident but not persistent and other emotions were expressed, or if the intensity of depression was moderate; and 3 (severe) if depressed mood was pervasive or persistent but of significant intensity.

Sleep disturbance (sleep disorder) is assessed based on the variation in the total amount of sleep during a 24-hour period, independent of external factors. It can manifest as insomnia (reduced total sleep time) or hypersomnia (increased total sleep time, including daytime sleepiness).

Insomnia was rated as 0 (no reduction in total sleep time); 1 (mild; reduction of up to 2 hours); 2 (moderate; 2-4 hours); and 3 (severe; more than 4 hours).

Alternative ratings of excessive sleep include 0 (no increase in total sleep time, including daytime sleep); 1 (mild; less than 2 hours, or normal amount but non-restorative); 2 (moderate; 2-4 hours); and 3 (severe; more than 4 hours).

Appetite disturbances are assessed based on changes in appetite and food consumption, independent of external factors. They can manifest as either a loss of appetite or an increase in appetite.

Loss of appetite was rated as 0 (no change in appetite or food consumption); 1 (mild; no change in food intake, but the patient had to force himself to eat or reported that food had no taste); 2 (moderate; some decrease in food intake); and 3 (significant decrease in food intake, with almost no food eaten).

Alternative ratings of increased appetite include 0 (no change in appetite or food consumption); 1 (mild; no change in food intake, but increased hunger); 2 (moderate; some increase in food intake, e.g., comfort eating); and 3 (marked increase in food intake or cravings).

Decreased social engagement was scored as 0 if there was no subjective report of decreased social and interpersonal engagement or interaction; 1 (mild) if social engagement was slightly reduced but social or interpersonal functioning was not impaired; 2 (moderate) if social engagement was markedly reduced with some functional sequelae, such as avoidance of some social engagements or conversations; and 3 (severe) if social interactions were markedly reduced or there was avoidance of almost all forms of social contact, such as refusing to answer phone calls or see friends or family.

Decreased energy and activity was scored as 0 if there was a decrease in energy, drive, or goal-directed behavior; 1 (mild) if the ability to perform usual activities was present but required increased effort; 2 (moderate) if energy was markedly reduced, resulting in a decrease in some specific role activities; and 3 (severe) if there was leaden paralysis or cessation of nearly all specific role activities (eg, spending excessive time in bed, avoiding telephone calls, poor personal hygiene).

Decreased motivation was scored as 0 if there was no report of a subjective decrease in drive, motivation, and consequent goal-directed activity; 1 (mild) if motivation was slightly reduced but functioning was not reduced; 2 (moderate) if motivation or drive was reduced and volitional activity was markedly reduced or great effort was required to maintain usual levels of functioning; and 3 (severe) if motivation or drive was reduced to the point where goal-directed behavior or functioning was markedly reduced.

If there is no subjective report of decreased attention, concentration, or memory, and no consequent functional impairment, the score for impaired concentration and memory is 0; if attention, concentration, or memory is slightly impaired but there is no functional impairment, the score is 1 (mild); if attention, concentration, or memory is severely impaired or forgetful with some functional impairment, the score is 2 (moderate); if concentration or memory is significantly impaired with significant functional impairment (e.g., inability to read or watch TV), the score is 3 (severe).

Anxiety was scored as 0 if there was no subjective report of worry, tension, and/or physical anxiety symptoms (e.g., tremors, palpitations, dizziness, vertigo, tingling, sweating, dyspnea, butterflies in the stomach, or diarrhea); 1 (mild; brief worry or tension over trivial matters); 2 (moderate; severe anxiety, tension, or worry, or some accompanying physical features); and 3 (severe; marked and persistent anxiety, tension, or worry that interferes with normal activities; or panic attacks).

Anhedonia was scored as 0 (no subjective reduction in the ability to experience pleasure in usual activities); 1 (mild; slightly reduced pleasure from normally pleasurable activities); 2 (moderate; markedly reduced pleasure from normally pleasurable activities; some retention of pleasure from isolated activities); or 3 (severe; complete inability to experience pleasure).

Affective apathy is scored as 0 if there is no subjective perception of a decrease in the intensity or range of feelings or emotions; 1 (mild) if there is a slight decrease in the range of emotions, or a temporary decrease in the range or intensity of feelings; 2 (moderate) if there is a significant decrease in the range or intensity of feelings, but some emotions are retained, such as an inability to cry; and 3 (severe) if there is a marked and pervasive decrease in the range of emotions, or an inability to experience usual emotions.

Feelings of worthlessness (also referred to simply as worthlessness) were scored as 0 (no subjective feelings or thoughts of self-worth or decreased self-worth); 1 (mild; slightly decreased self-worth); 2 (moderate; some feelings of worthlessness and thoughts of decreased self-worth); and 3 (severe; marked, pervasive, or persistent feelings of worthlessness, e.g., feeling that others would be better off without you, inability to appreciate positive qualities).

Feelings of helplessness and hopelessness (also referred to simply as helplessness and hopelessness) characterize a subjective feeling of pessimism or depression about the future, inability to cope, or a feeling of loss of control. If absent, the score is 0. If the feeling of being unable to cope as usual or pessimism occurs occasionally and is mild, the score is 1 (mild); if the patient often feels unable to cope, or has a significant feeling of helplessness or hopelessness, but sometimes disappears, the score is 2 (moderate); if there is a significant and persistent feeling of pessimism, helplessness, or hopelessness, the score is 3 (severe).

Suicidal ideation is related to thoughts or feelings that life is worthless, thoughts about death, or suicide, and is scored as 0 if there are no such thoughts; 1 (mild) if there are thoughts that life is worthless or meaningless; 2 (moderate) if there are thoughts about dying or death but no active suicidal thoughts or plans; and 3 (severe) if there are suicidal thoughts or plans.

Feelings of guilt (also referred to simply as feelings of guilt) were scored as 0 if there were no subjective feelings of self-blame, failure, or regret for past real or imagined mistakes; 1 (mild) if there was a slight decrease in self-esteem or increased self-criticism; 2 (moderate) if there were clear thoughts of failure, self-criticism, inability to cope, or rumination about past failures and their impact on others, with an ability to recognize excesses; and 3 (severe) if there was a clear, pervasive, or persistent feeling of guilt, such as feeling like one should be punished; or if there was no clear recognition of excesses.

If there are no overvalued thoughts, delusions, or hallucinations, the score for psychotic symptoms is 0; if there are mild overvalued thoughts, such as self-criticism or pessimism, but no obvious impact on behavior, the score is 1 (mild); if there are significant overvalued thoughts and a clear impact on behavior, such as strong feelings of guilt and clear beliefs that others would be better off without them, the score is 2 (moderate); if there are obvious psychotic symptoms, such as delusions or hallucinations, the score is 3 (severe).

Irritability reported atypical subjective irritability, short temper, and easy anger, manifested by verbal or physical outbursts, and was scored as 0 if there was none; 1 (mild) if there was mild subjective irritability, which might not be very obvious; 2 (moderate) if verbal impatience and irritability were clearly observed during the interview; and 3 (severe) if physical outbursts were reported, such as throwing/breaking objects, or obvious abusive verbal outbursts.

If no mood lability was observed or mood swings were reported, the instability score was 0. If the subjective report of mood lability was mildly increased, it was scored as 1 (mild); if mood lability was clearly observed, it was scored as 2 (moderate); if mood lability was obvious and dominant, and mood swings were frequent or intense, it was scored as 3 (severe).

Increased exercise drive involves subjective reports and objective evidence of increased drive to exercise and motor activity. If exercise drive is normal, it is scored as 0; if drive is slightly increased but not observable during the interview, it is scored as 1 (mild); if the increase in energy and drive is significant and observable, it is scored as 2 (moderate); if the increase in drive is marked or persistent, it is scored as 3 (severe).

Increased speech involves the observation of an increase in the rate or volume of speech, or the observation of racing thoughts. This item is scored as 0 if no such observations are made; 1 (mild) if there is a slight increase in the rate or volume of speech; 2 (moderate) if thoughts are racing, or the patient is noticeably more talkative, noticeably easily distracted, or there is some verbosity, which does not interfere with the interview; and 3 (severe) if the racing thoughts interfere with the interview.

Agitation was scored as 0 if no fidgeting or agitation was observed, 1 (mild) if there was mild fidgeting, 2 (moderate) if there was a marked increase in agitation, and 3 (severe) if there was marked agitation, such as almost continuous pacing or hand-wringing.

Although higher scores on the BDRS scale indicate more severe illness, there are no universally accepted cutoffs for when a patient is considered moderately or severely ill. The BDRS score range used in this article to represent the severity of depressive episodes in patients with bipolar disorder is: 13-18 as "mildly ill," 19-23 as "moderately ill," 24-36 as "somewhat ill," 37-39 as "severely ill," and ≥40 as "extremely ill."

Various other scales are also available to assess disease severity and clinical outcomes of treatment.

The CGI was developed to provide a brief, independent assessment of the clinician's perception of a patient's global functioning before and after treatment (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

The CGI severity (CGI-S) is based on a single question that clinicians must answer: “Given your overall clinical experience with this particular population, how ill is the patient currently?” Rated on a seven-point scale: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = somewhat severely ill; 6 = severely ill; and 7 = the sickest patient.

The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has an equally simple format. After treatment, the clinician compares the patient's overall clinical condition with the condition before treatment (the so-called baseline value). Again, there is only one inquiry rated on a seven-point scale: "Compared with the patient's condition at admission (before starting medication), is this patient's condition: 1 = very much improved since starting treatment; 2 = much improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worse; 6 = a lot worse; 7 = very much worse since starting treatment."

The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is the counterpart of the Clinical Global Impression (CGI). It consists of one item based on the CGI and adapted for the patient. It can measure disease severity (PGI-S) or disease improvement (PGI-I).

The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, S.A. and Asberg, M. (1979). A new depressionscale designed to be sensitive to change. The British Journal of Psychiatry 134, p. 382). It is designed as an adjunct to the Hamilton Depression Rating Scale (HAM-D) and will be more sensitive to changes brought about by antidepressants and other forms of treatment. The higher the MADRS score, the more severe the depression. The items considered are obvious sadness; reported sadness; inner tension; decreased sleep; decreased appetite; difficulty concentrating; laziness; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item is scored from 0 to 6. The total score ranges from 0 to 60. The score range used in this article to assess the severity of depressive episodes in patients with bipolar disorder is: 13-18 for "mild illness", 19-23 for "moderate illness", 24-36 for "severe illness", 37-39 for "severe illness", and ≥40 for "extremely severe illness" (Thase, 2021).

Using a structured interview guide (SIGMA) for MADRS will improve the reliability of a given scale (Williams, J.B.W and Kobak, K.A., 2008. Development and reliability of a structured interview guide for the Montgomery Asberg Depression Rating Scale (SIGMA). The British Journal of Psychiatry 192, p. 52; Freeman, M.P, Pooley, J., Flynn, M.J., Baer, L, Mischoulon, D., Mou, D. and Fava, M., 2017. Guarding the Gate. Remote Structured Assessments to Enhance Enrollment Precision in Depression Trials. Journal of Clinical Pharmacology 37(2), p. 176).

The Hamilton Depression Rating Scale (Ham-D) is a clinician-administered depression assessment scale. The original version contained 17 items related to depressive symptoms (HDRS17) (Hamilton, M., 1960. A Rating Scale for Depression, J Neurol Neurosurg Psychiatry 23: 56-62; Hamilton, M., 1967. Development of a rating seale for primary depressive illness. Br J Soc Clin Psychol 1967; 6 (4): 278-96). Although the scale was designed to be completed after an unstructured clinical interview, a semi-structured interview guide is now available (Williams, J.B., 1988. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 45 (8): 742-7). The subsequent 21-item version includes 4 items designed to subtype depression.

The Young Mania Rating Scale (YMRS; Young, R.C., Biggs, J.T., Ziegler, V.E. and Meyer, D.A. (1978). A rating scale for mania: reliability, validity and sensitivity. The British journal of psychiatry, 133 (5), 429-435) is one of the most commonly used rating scales for assessing manic symptoms. The scale has 11 items and is based on the patient's subjective report of his or her clinical condition over the past 48 hours. Additional information is based on clinical observations made during the clinical interview. Items are selected based on published descriptions of core symptoms of mania. The YMRS follows the style of the HAM-D, with a severity rating given to each item. Four items are rated on a scale of 0 to 8 (irritability, speech, thought content, and destructive/aggressive behavior), while the remaining seven items are rated on a scale of 0 to 4. These four items are given twice the weight of the other items to compensate for the lack of cooperation of seriously ill patients. Each severity level has clearly described anchor points. Once experience with the scale is gained, the authors encourage the use of whole-point or half-point ratings. The scale is typically completed by a clinician or other rater who is trained and has expertise in patients with mania.

Brief Psychiatric Rating Scale (BPRS) is designed to screen psychotic symptoms in a structured manner. The scale is one of the most widely used scales for measuring psychotic symptoms and was first published in 1962. The design was later updated. The most commonly used version today includes 18 different areas for evaluation by doctors or psychologists (in general, J.E. and Gorham, D.R., 1962. The brief psychiatric rating scale. Psychological Reports 10, p. 799; in general, J.E. and Gorham, D.R., 1988. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacology Bulletin 22, p. 97).

Eighteen items (somatic focus, anxiety, emotional withdrawal, conceptual confusion, guilt, tension, mannerisms and postures, grandiosity, depressed mood, hostility, suspiciousness, hallucinatory behavior, bradykinesia, uncooperativeness, unusual thought content, blunted affect, excitement, and disorientation) were scored, and each item was rated on a scale of 1-7.

The doctor or psychologist will complete two tasks during the approximately 15-minute interview with the patient:

· They will ask the patient a series of questions from a list.

They will check to see if the patient exhibits certain behaviors.

Based on the answers and observed behaviors, the physician or psychologist will complete the BPRS form by ranking the severity of each domain using a scale of one to seven: one means no sign or symptom is present, and seven means the sign or symptom is present and at a severe level. If a specific sign or symptom cannot be rated, a score of 0 or "not assessed" is recorded.

The Clinically Administered Dissociative States Scale (CADSS) is assessed by the researcher through interviews with the patients. The CADSS is a 27-item scale with 19 subject-rated items and 8 observer-rated items. The rating range is 0 "not at all" to 4 "extremely" (Bremner, J.D., Krystal, J.H., Putnam, F.W., Southwick, S.M., Marmar, C., Charney, D.S., and Mazure, C.M., 1998. Measurement of Dissociative States with the Clinician-Administered Dissociative States Scale (CADSS). Journal of Traumatic Stress 11 (1), p. 125).

The CADSS is divided into 3 components: 1) Depersonalization, 2) Derealization, and 3) Amnesia. These subscales are summed together to form a total dissociation score. The CADSS was specifically designed to serve as a standardized measure of current state dissociative symptomatology.

The Columbia-Suicide Severity Rating Scale (C-SSRS) is a detailed questionnaire that assesses suicidal behavior and suicidal ideation to help identify the need for immediate medical intervention and to provide data for an overall assessment of the effectiveness of treatments related to suicidality. The C-SSRS is evidence-based and is part of national and international public health initiatives involving the assessment of suicidality (Posner, K., Brown, G.K., Stanley, B., Brent, D.A., Yershova, K.V., Oquendo, M.A., Currier, G.W., Melvin, G.A., Greenhill, L, Shen, S., and Mann, J.J., 2011. The Columbia-Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults. American Journal of Psychiatry 168(12), pp. 1266-77).

The questionnaire will be administered in the form of an interview by a registered psychologist or medical doctor.

The present invention provides for the treatment of patients diagnosed with bipolar disorder, especially bipolar disorder type II, as defined herein, and in particular patients diagnosed with bipolar disorder suffering from a current major depressive episode. The treatment includes in particular the treatment of the above-mentioned aspects of the disease, namely sleep disturbances, psychomotor retardation (reduced energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory) and social/emotional withdrawal or alienation (anhedonia, emotional withdrawal and emotional apathy).

The treatment also counteracted suicidal ideation. In addition, the treatment also improved mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation).

The present invention specifically provides for the treatment of depression in BD patients without inducing hypomania or mania.

Active Agent

The above discussion shows that BD is characterized by several aspects, which in themselves carry a significant disease burden and require appropriate treatment. Therefore, treatments are needed not only to improve the overall disease score (especially through pharmacological interventions), but also to improve specific aspects of the disease.

The inventors believe that carefully selected hallucinogens may lead to improved treatment of important aspects of BD, and may result in overall improvement of the disease.

A group of hallucinogens comprises compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families with several subtypes are described, 5-HT1 to 5-HT7). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agents are often referred to as "psychedelics", which emphasizes their primary ability to induce qualitative changes in states of consciousness, such as euphoria, trance, time and space, spiritual experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, with the indoleamines divided into two subsets, the ergoline and the tryptamines, the latter of which are derived from tryptamine.

Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activities may also be modulated through interactions with other targets such as monoamine transporters and trace amine-associated receptors.

Recently published studies on the use of serotonergic psychedelics such as LSD, psilocybin, and DMT (the shamanic medicine ayahuasca) in certain psychiatric disorders suggest that these compounds may offer an alternative approach to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, and this may preclude their use in the treatment of BD patients.

For example, Lake et al. (Lake, C.R., Stirba, A.L., Kinneman, R.E.Jr, Carlson, B., Holloway, H.C., 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11): 1508-9) reported a patient who experienced a manic episode after taking LSD or an LSD analog. The patient experienced symptoms of acute LSD intoxication, which were relieved, but a typical psychotic manic episode occurred about 3 weeks later. Hendin and Penn (Hendin, H.M., Penn, A.D., 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4): 1-3) reported a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, A.G., Valerio, M.P. and Jose M Smith, J.M., 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a man with bipolar disorder who switched to mania after drinking ayahuasca, a beverage containing DMT.

Another case report can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Comelius, C. (2017). A Physician’s attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

The inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, especially in the treatment of BD patients, the administered compound must be appropriately selected and preferably administered according to a specific dosing regimen.

The inventors have determined that 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic drug of particular interest for the treatment of bipolar disorder and various aspects thereof. 5-MeO-DMT has unique pharmacological properties that are different from other psychedelic drug compounds.

5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype than other classic psychedelics.

As further detailed in the Examples section below, the inhibition constants (Ki values) of psilocin (the dephosphorylated form of psilocybin formed after ingestion of psilocybin), DMT, and 5-MeO-DMT at the 5-HT1A receptor located in the hippocampus of postmortem human brains are 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while psilocin and DMT exhibit moderate affinity. The inhibition constants ( _{Ki values} ) of psilocin, DMT, and 5-MeO-DMT at the 5-HT2A receptor located in the frontal cortex of postmortem human brains are 37, 117, and 122 nM, respectively. Thus, psilocin exhibits moderate/strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for the 5-HT1A receptor, where 5-MeO-DMT acts as a potent agonist. Relative to 5-MeO-DMT, the contribution of 5-HT2A binding is increased in the case of dephosphorylated psilocybin and DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Thus, 5-HT1A binding relative to 5-HT2A binding plays a much larger role in the overall effects of 5-MeO-DMT than the other two compounds.

5-HT1A agonists reportedly reduce impulsivity and aggression, while 5-HT2A agonists can cause short-term increases in these same traits. Additionally, the dopamine system has been implicated in causing mania, with increases in dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

Compared to other psychedelics (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using a dosing regimen as described herein without producing a significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders and treated according to the present invention do not experience treatment-induced mania or hypomania.

It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate use of a large number of the corresponding compounds (e.g., DMT/ayahuasca, psilocybin, LSD).

The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

Further, antidepressants have been reported to induce isolated hypomanic episodes in patients with treatment-resistant depression (TRD) (Bader, Cynthia D. and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of induction of hypomania.

5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective, described as a "loss of self," typically ending in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after inhalation, compared to hours with, e.g., oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific alterations in resting state network (RSN) activity under 5-MeO-DMT treatment.

Specifically, the default mode network, one of several RSNs, is associated with a variety of psychiatric disorders, and abnormal connectivity in these disorders has been confirmed by functional MRI. This has been noted in bipolar disorder (Chai et al. 2011, Wang et al. 2016), although combined with a variety of distinctive connectivity patterns and/or corticolimbic connections (e.g., between the prefrontal cortex and the amygdala (de Almeida 2009)) between several other RSNs (Rai, 2021), this appears to distinguish bipolar depression from unipolar depression. Although the involvement of the DMN and other RSNs in bipolarity may be different from that in unipolarity, the presence of abnormal connectivity combined with the improvements observed in BD-related symptoms and the lack of induction of manic episodes in recent clinical trials has led the inventors to conclude that 5-MeO-DMT is suitable for the treatment of bipolar disorder, especially when administered as described herein.

Various aspects of bipolar disorder, such as sleep disturbance, psychomotor retardation (decreased energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social/emotional withdrawal or alienation (anhedonia, emotional withdrawal, and emotional flattening) can be improved. Additional aspects of the disorder that can be improved include suicidal ideation and mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation). The improvements that can be achieved are reflected on clinically relevant scales.

Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be administered to BD patients using a dosing regimen as described herein without a significant risk of inducing mania or hypomania.

Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. The inventors used recombinant human 5-HT7 receptor, [ ³ H]LSD as radioligand and serotonin to estimate nonspecific binding and determined a K _i of 2.3 nM.

Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis and dendritic spine formation. It is associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

5-HT7 receptors are expressed particularly in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus (including the suprachiasmatic nucleus), hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination leads to disease states, particularly those involving sleep disturbances. In patients with sleep disturbances, resting-state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of said receptors in regulating the sleep/wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

The inventors believe that the combination of 5-MeO-DMT and the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social/emotional withdrawal. This is supported by the clinical results shown in the studies cited herein.

Another characteristic of 5-MeO-DMT is its short half-life.

5-MeO-DMT is primarily inactivated through a monoamine oxidase A-mediated deamination pathway and is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

The inventors studied the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

The properties of 5-MeO-DMT make the compound particularly suitable for treating BD, such as bipolar disorder type II, especially for patients suffering from a current major depressive episode.

The properties of 5-MeO-DMT also allow for specific dosing regimens, as discussed in more detail below.

According to the present invention, isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used.When referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

A deuterated form of 5-MeO-DMT is one that contains more deuterium than would be expected based on the natural abundance of this isotope.

The deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethylamine.

Further examples include forms of 5-MeO-DMT in which deuterium has been introduced at one or more hydrogen positions of the N-bound methyl group. Still further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is also worth noting that combinations of the above substitution patterns are also contemplated.

Methods for the preparation of these compounds are known in the art.

Mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

Furthermore, according to the present invention, the amount of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used is equimolar to the amount of the corresponding non-deuterated form.

According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be converted to 5-MeO-DMT by metabolism. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be used instead.

In a suitable prodrug, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

Examples of suitable organic moieties are C(O) ^OR1 , -C(O) ^R2 , -CH( ^R3 ) ^OR4 , -C(O)OCH( ^R3 )OC(O) ^R4 , -C(O)OCH( ^R3 )OC(O) ^OR4 , -CH( ^R3 )C(O) ^R4 , -CH( ^R3 )OC(O) ^R4 , -CH( ^R3 )OC(O) ^OR4 , wherein each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted or unsubstituted.

Preferred examples of organic moieties are -CH(R ³ )OC(O)R ⁴ and -C(O)OR ¹ , wherein R ¹ , R ³ and R ⁴ are as defined above.

Prodrugs, especially those of the above structure, can also be used in the form of pharmaceutically acceptable salts.

Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

Methods for preparing prodrugs as discussed herein are known in the art.

According to the present invention, the _Tmax value of the metabolite 5-MeO-DMT measured after oral administration of the prodrug at 10 mg/kg in male Sprague-Dawley (SD) rats is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

patient

Patients treated according to the present invention are diagnosed as suffering from bipolar disorder by licensed professionals according to generally accepted medical practices. For example, the diagnosis can be made according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association.

In one aspect, the patient is diagnosed with bipolar disorder type II. In another aspect, the patient is diagnosed with bipolar disorder type I.

Typically, people diagnosed with either bipolar II or bipolar I are experiencing a current major depressive episode.

The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient may have a total score equal to or greater than 19, such as greater than or equal to 24, in particular greater than or equal to 37.

Alternatively or additionally, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as greater than or equal to 24, in particular greater than or equal to 37.

Further alternatively or additionally, the patient may have a Hamilton Depression Rating Scale (HAM-D) total score of 19, such as greater than or equal to 24, in particular greater than or equal to 37.

The patient may suffer from a treatment-resistant disease. Treatment resistance means that the patient has not adequately improved after at least two adequate courses of treatment. The patient has not adequately improved after at least two adequate courses of treatment, in particular, wherein at least one of the two courses is drug therapy; for example, the patient has not adequately improved after at least two adequate courses of drug therapy. In particular, at least two previous courses of treatment were administered during the current depressive episode.

Patients with a major depressive episode treated in accordance with the present invention will typically have a Young Mania Rating Scale (YMRS) total score of 8 or less.

Treatment for BD

As indicated above, treatment according to the present invention relates to various aspects of bipolar disorder.

These include sleep disturbances, psychomotor retardation (decreased energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social/emotional withdrawal or detachment (anhedonia, emotional withdrawal, and affective flattening).

The treatment also counteracted suicidal ideation. In addition, the treatment also improved mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased verbalization; agitation).

Treatment of patients suffering from bipolar disorder according to the present invention will generally involve more than one of the above aspects. Treatment will generally result in a clinical response in several or all of the above aspects with an overall improvement.

According to the invention, the above aspects can also be treated if they occur independently of bipolar disorder, for example in the context of a different psychiatric disorder. A clinical response can be achieved regardless of whether the patient has been diagnosed with bipolar disorder.

Treatment according to the invention alleviates or eliminates (or improves or eliminates) one aspect of the disease. As used herein, this means that if the aspect is assessed on the BDRS scale, there is at least one point of improvement (mitigation) or the patient is in complete remission (elimination) after treatment, i.e. the corresponding aspect score is 0.

If the domain is assessed on the MADRS scale, there is an improvement of at least one point (reduction) or the patient is in complete remission (elimination) after treatment, i.e. the corresponding domain score is 0.

If there is at least one point improvement (reduction) in the BPRS scale for that aspect or the patient is completely relieved (eliminated) after treatment, the corresponding aspect score is 1.

The clinical response can also be reflected as a reduction in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 point. Preferably, the CGI-S is reduced by at least 2 points and/or to 0 points. Particularly preferably, the CGI-S is reduced by at least 3 points and/or to 0 points.

To further support the clinical utility of 5-MeO-DMT in patients suffering from BD, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in aspects of the disease that are also commonly observed in patients suffering from bipolar disorder. The inventors particularly noted improvements in various symptoms and combinations of symptoms that are unique to BD.

The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below.) Although TRD is a distinct disorder from BD, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for BD.

In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

The data collected included assessments of the treated patients for several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate therapeutic efficacy through improvements in overall MADRS scores, the inventors focused on the items that make up the various rating scales and noted overlap between several of these sub-scoring items and the symptoms outlined above, which is particularly noteworthy in BD patients. Multiple patients in the recruited cohort showed significant improvements in one or more of these sub-scoring items, a result that confirms the inventors' findings that 5-MeO-DMT is a compound suitable for treating BD patients, particularly BD patients who experience these symptoms.

The specific sub-scoring items in each scale are identified in more detail below. While these items do not always provide an exact match to the BD-related symptoms outlined above, the inventors recognize that there is overlap between these items and those symptoms and conclude that improvements noted for these items will translate to improvements for related symptoms that have been specifically included in BD-specific assessment scales, such as the BDRS. Indeed, given the level of support in the literature for the association of these symptoms with BD, the inventors conclude that efficacy in treating one or more of these symptoms will result in significant improvements in the overall outcome of BD patients treated with 5-MeO-DMT.

One aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is sleep disturbance. 5-MeO-DMT can be administered to BD patients to improve the patient's sleep quality.

Sleep disturbances, including changes in total sleep time (insomnia/hypersomnia) and circadian rhythm abnormalities, are particularly noted in patients with bipolar disorder, as described by Kaplan et al., Gottlieb et al., and others.

Further studies have shown that the default mode network (DMN) is associated with sleep disruption (De Havas et al.; Nie et al.). The inventors believe that the association between the DMN and sleep disruption and the effects of 5-MeO-DMT on the DMN after appropriate administration and dosing suggest that sleep disorders may be treated with 5-MeO-DMT.

In the clinical studies mentioned above involving the administration of 5-MeO-DMT, the MADRS item "sleep reduction" reflecting insomnia was evaluated, among others.

The MADRS item "Sleep reduction" represents the experience of reduced sleep duration or depth compared to the normal pattern of the subject's own health. When the subject's sleep is normal, the score is 0. A score of 2 reflects mild difficulty falling asleep, or slightly reduced, shallow or intermittent sleep time. A score of 4 means that sleep time is reduced or interrupted by at least two hours. A score of 6 means less than two or three hours of sleep.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "reduced sleep" was 25 at baseline for all eight patients. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score decreased to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score decreased to 9, which corresponds to an improvement of 16 points or 64%.

In the 12 mg group, the total score of the MADRS item "reduced sleep" for all 4 patients was 12 at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

Thus, the score of the scale item "sleep reduction" which is particularly related to sleep disturbance was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat sleep disturbance in patients, especially patients suffering from psychiatric disorders such as BD.

Thus, according to the present invention, treating a patient suffering from a sleep disorder with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorder.

Reduction or elimination of sleep disturbances can be reflected at least in an improvement in the score of the BDRS item sleep disturbances on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of sleep disturbance (reflected by an improvement in the score of the BDRS item sleep disturbance) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbance (reflected by an improvement in the score of the BDRS item sleep disturbance) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the sleep disturbance is sleep loss, the reduction or elimination of the sleep disturbance can be reflected in at least an improvement in the score of the MADRS item sleep loss on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of sleep disturbances (reflected as an improvement in the score of the MADRS item sleep reduction) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances (reflected as an improvement in the score of the MADRS item sleep reduction) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the patient suffers from sleep disturbance, improvement in sleep disturbance is reflected in a decrease in Clinical Global Impression-Severity (CGI-S) score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in sleep disturbance, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in sleep disturbance (as reflected at least by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in sleep disturbance (at least reflected by a decrease in the CGI-S score or a score of "much improved" in the CGI-I score or the PGI-I score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As mentioned above, sleep disturbance is an item of BDRS. Since sleep disturbance also affects other aspects of BD, the inventors concluded that the observed improvement in the score of the "sleep reduction" item on MADRS will not only bring about an associated improvement in the score of the "sleep disturbance" BDRS scale item, but also promote an overall improvement in the BDRS score.

If the patient suffers from sleep disturbances, reduction or elimination of sleep disturbances is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the time point at which the acute psychedelic experience subsides after the last administration to the assessment time point.

If the patient suffers from sleep disturbance, then the reduction or elimination of sleep disturbance (reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the time point at which the acute psychedelic experience resolves after the last administration to the assessment time point. The reduction or elimination of sleep disturbance (reflected by an improvement in the PSQI score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Another aspect of bipolar disorder (especially bipolar II disorder) that can be treated by administering 5-MeO-DMT is psychomotor retardation, that is, a combination of decreased energy and activity and decreased motivation. Psychomotor retardation involves a slowing of the individual's thinking and decreased physical movement. Psychomotor disorders can cause a significant slowing of physical and emotional reactions. Psychomotor retardation has been noted in patients suffering from bipolar disorder. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's psychomotor retardation, that is, to counteract decreased energy and activity and decreased motivation.

In the clinical study mentioned above involving the administration of 5-MeO-DMT, the MADRS item "sluggishness" was assessed, among others.

"Sloth" means difficulty or slowness in initiating and performing daily activities.

A score of 0 means starting with almost no difficulty and no sluggishness. If the patient has difficulty starting an activity, the score is 2. A score of 4 means difficulty starting simple daily activities that require effort. If the patient is completely lazy and cannot do anything without help, the score is 6.

This MADRS scale item is particularly relevant to psychomotor retardation (ie, decreased energy and activity and decreased motivation).

In the study group that received the individualized dosing regimen, the total score for the MADRS item “laziness” was 27 at baseline for all eight patients.

After 2 hours, the score dropped to 10, which corresponds to 17 points or 63% improvement. On the first day after treatment, the score dropped to 5, which corresponds to 22 points or 81% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to 24 points or 89% improvement.

In the 12 mg group, the total score of the MADRS item "slouching" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 6 points or 38%. On the first day after treatment, the score dropped to 0, which corresponds to an improvement of 16 points or 100%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

Thus, the score of the scale item "sloth" which is particularly relevant to psychomotor retardation was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat psychomotor retardation in patients, especially those suffering from psychotic disorders such as BD, i.e. to combat decreased energy and activity and decreased motivation.

Thus, according to the present invention, treatment of a patient suffering from psychomotor retardation reduces or eliminates psychomotor retardation. Treatment improves or eliminates decreased energy and activity and/or decreased motivation.

Reduction or elimination of psychomotor retardation can be reflected as an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the BDRS items reduced energy and activity and/or reduced motivation) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the BDRS items reduced energy and activity and/or reduced motivation) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of psychomotor retardation may be reflected as an improvement in the score of the MADRS item lazyness at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the MADRS item lazy) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the MADRS item lazy) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the patient suffers from psychomotor retardation, improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14 and/or on day 28.

Improvement in psychomotor retardation, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in psychomotor retardation (as reflected at least by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in psychomotor retardation (reflected at least by a decrease in the CGI-S score or a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As mentioned above, "reduced energy and activity" and "reduced motivation" are items of BDRS. Since psychomotor retardation also affects other aspects of BD, the inventors concluded that the observed improvement in the score of the "laziness" item on MADRS will not only bring about a related improvement in the score of the "reduced energy and activity" and/or "reduced motivation" BDRS scale items, but also contribute to the overall improvement of the BDRS score.

Another aspect of bipolar disorder (particularly bipolar II disorder) that can be treated by administering 5-MeO-DMT is negative thinking, including feelings of worthlessness; feelings of helplessness and hopelessness; and feelings of guilt. 5-MeO-DMT can be administered to BD patients to reduce or eliminate such symptoms in the patients.

Symptoms such as pessimism, feelings of worthlessness, and feelings of helplessness and hopelessness have been noted in patients with bipolar disorder. In addition, BD patients have been reported to be more prone to morbid, excessive, or inappropriate guilt than MDD patients.

These symptoms are collectively referred to as negative thinking in this article.

A MADRS scale item that is particularly relevant to this aspect of BD is “pessimistic thoughts,” which represents thoughts of guilt, low self-esteem, self-condemnation, sin, regret, and destructiveness.

If there are no pessimistic thoughts, the score is 0. If there are fluctuating ideas of failure, self-condemnation, or self-deprecation, the score is 2. A score of 5 implies persistent self-blame, or clear but still rational ideas of guilt or sin, and the patient's increasing pessimism about the future. If there are delusions of destruction, remorse, or irreparable guilt and absurd and unshakable self-blame, the score is 6.

In the study group that received the individualized dosing regimen, the total score for the MADRS item “pessimistic thoughts” was 28 at baseline for all eight patients.

After 2 hours, the score dropped to 7, which corresponds to 21 points or 75% improvement. On the first day after treatment, the score dropped to 4, which corresponds to 24 points or 86% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to 25 points or 89% improvement.

In the 12 mg group, the total score for the MADRS item "pessimistic thoughts" was 16 at baseline for all four patients. After 2 hours, the score dropped to 8, which corresponds to an improvement of 8 points or 50%. On the first day after treatment, the score dropped to 7, which corresponds to an improvement of 9 points or 56%.

On day 7 after treatment, the score dropped to 8, which corresponds to an improvement of 8 points or 50%.

The BPRS item that is particularly relevant to guilt is "Guilt Feelings." This item is related to excessive concern or regret about past behavior. Possible ratings are:

1- No guilt.

2 - Very Mild. Worries about disappointing someone or failing at something, but is not preoccupied. Can easily shift thoughts to other things.

3 - Mild. Some concern about disappointing someone or failing at something, some preoccupation. Tends to express guilt to others.

4 - Moderate. Preoccupied with guilt, guilt, or hurting others by something they did or did not do, but easily able to shift attention to other things.

5 - Moderate to severe. Preoccupied with guilt, disappointing someone, or failing at something; attention can be directed to other things but requires considerable effort. Not delusional.

6-Severe; delusional guilt or irrational self-condemnation that is highly disproportionate to actual situation. Moderate preoccupation present.

7 - Extreme. Delusional guilt or irrational self-condemnation that is totally disproportionate to the actual situation. The subject is extremely preoccupied with guilt and may disclose the delusion to others or act on it.

In the study group that received the individualized dosing regimen, the total score for the BPRS item “guilt” was 34 at baseline for all eight patients.

After 3 hours, the score dropped to 14, which corresponds to a 20-point or 59% improvement. On day 1 after treatment, the score dropped to 11, which corresponds to a 23-point or 68% improvement. On day 7 after treatment, the score dropped to 10, which corresponds to a 24-point or 71% improvement.

In the 12 mg group, the total score of the BPRS item “guilt” was 18 at baseline for all 4 patients.

After 3 hours, the score dropped to 9, which corresponds to 9 points or 50% improvement. On the first day after treatment, the score dropped to 5, which corresponds to 13 points or 72% improvement. On the seventh day after treatment, the score dropped to 5, which corresponds to 13 points or 72% improvement.

Thus, the score of the MADRS scale item "pessimistic thoughts" which is particularly related to negative thinking was significantly improved, and the score of the BPRS item "guilt" was also significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat negative thinking in patients, especially patients suffering from mental illnesses such as BD.

Thus, according to the present invention, treatment of a patient suffering from negative thinking reduces or eliminates the negative thinking. Treatment reduces or eliminates feelings of worthlessness; feelings of helplessness and hopelessness; and/or feelings of guilt.

A reduction or elimination of negative thoughts can be reflected at least in an improvement in scores on the BDRS items worthlessness; helplessness and hopelessness; and/or guilt at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of negative thoughts (reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of negative thoughts (reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of negative thoughts may be reflected at least in an improvement in the score of the MADRS item pessimistic thoughts at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of negative thoughts (reflected as an improvement in the score of the MADRS item pessimistic thoughts) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of negative thoughts (reflected as an improvement in the score of the MADRS item pessimistic thoughts) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of negative thoughts may be reflected at least in an improvement in the score of the BPRS item guilt at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of negative thoughts (reflected by an improvement in the score of the BPRS item Guilt) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of negative thoughts (reflected by an improvement in the score of the BPRS item Guilt) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the patient suffers from negative thinking, improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14 and/or on day 28.

Improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in negative thinking (as assessed by at least a "much improved" score on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in negative thinking (reflected at least by a decrease in the CGI-S score or a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As mentioned above, helplessness and hopelessness; worthlessness; and guilt are all items of the BDRS. Since negative thinking also affects other aspects of BD in addition, the inventors concluded that the observed improvements in the scores of the "pessimistic thoughts" item on the MADRS and the "guilt" item on the BPRS will not only bring about related improvements in the scores of the "worthlessness", "helplessness and hopelessness" and/or "guilt" BDRS scale items, but also promote the overall improvement of the BDRS score. For example, the BDRS item "psychotic symptoms" includes strong guilt as a contributing factor.

Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's anxiety.

The BPRS item that is particularly relevant to anxiety is "Anxiety." This item is related to reported worry, nervousness, fear, panic, or concern. Possible scores are

1- No Anxiety

2 - Very Mild. Reports some discomfort due to worry or infrequent worry that occurs more frequently than in most normal individuals.

3 - Mild. Frequent worrying but able to easily shift attention to other things.

4-Moderate. Worried most of the time and unable to easily redirect attention, but functioning is not impaired; or anxious occasionally with autonomic symptoms, but functioning is not impaired.

5 - Moderate to severe. Frequent (but not daily) anxiety with autonomic symptoms or some areas of functioning are disrupted by anxiety or worry.

6 - Severe. Anxiety is daily with autonomic symptoms, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or persistent worry.

7 - Extreme. Anxiety with autonomic symptoms persists throughout the day, or most areas of functioning are disrupted by anxiety or persistent worry.

In the study group that received the individualized dosing regimen, the total score for the BPRS item “anxiety” was 37 at baseline for all eight patients.

After 3 hours, the score dropped to 19, which corresponds to an improvement of 18 points or 49%. On the first day after treatment, the score dropped to 16, which corresponds to an improvement of 21 points or 57%. On the seventh day after treatment, the score dropped to 17, which corresponds to an improvement of 20 points or 54%.

In the 12 mg group, the total score of the BPRS item “anxiety” was 25 at baseline for all 4 patients.

After 3 hours, the score dropped to 11, which corresponds to an improvement of 14 points or 56%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%.

The inventors concluded that 5-MeO-DMT could be used to treat anxiety in patients, particularly those suffering from psychiatric disorders such as BD.

Thus, according to the present invention, treatment of a patient suffering from anxiety reduces or eliminates the anxiety.

Reduction or elimination of anxiety may be reflected in at least an improvement in BDRS item anxiety 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

The reduction or elimination of anxiety (reflected as an improvement in the BDRS item anxiety) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety (reflected as an improvement in the BDRS item anxiety) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of anxiety is reflected in at least an improvement in BPRS item anxiety at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of anxiety (reflected in an improvement in the BPRS item anxiety) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety (reflected in an improvement in the BPRS item anxiety) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the patient suffers from anxiety, improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in anxiety (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in anxiety (at least reflected by a decrease in the CGI-S score or a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As mentioned above, "anxiety" is an item of BDRS. Since anxiety also affects other aspects of BD, the inventors concluded that the observed improvement of the "anxiety" item on BPRS will not only bring about a related improvement of the "anxiety" BDRS scale item, but also promote an overall improvement in the BDRS score.

Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is cognitive dysfunction, particularly difficulty concentrating. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's cognitive dysfunction, particularly difficulty concentrating.

Patients with bipolar depression show impairments in the areas of memory and executive function, with evidence suggesting that bipolar depressed subjects have poorer executive functioning compared with unipolar depressed subjects. In addition, psychomotor retardation has been reported to be accompanied by a cognitive component in bipolar patients.

A MADRS item that is particularly relevant to impairments in concentration and memory is “difficulty concentrating.”

This item represents difficulty organizing thoughts, escalating to inability to concentrate. If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty organizing thoughts, the score is 2. If there is difficulty concentrating and maintaining thoughts, resulting in a decrease in the ability to read or hold a conversation, the score is 4. If the patient cannot read or talk easily, the score is 6.

In the study group that received the individualized dosing regimen, all eight patients had a total score of 30 for the MADRS item “difficulty concentrating” at baseline.

After 2 hours, the score dropped to 11, which corresponds to 19 points or 63% improvement. On the first day after treatment, the score dropped to 1, which corresponds to 29 points or 97% improvement. On the seventh day after treatment, the score dropped to 9, which corresponds to 21 points or 70% improvement.

In the 12 mg group, the total score for the MADRS item “difficulty concentrating” was 16 at baseline for all four patients.

After 2 hours, the score dropped to 7, which corresponds to 9 points or 56% improvement. On the first day after treatment, the score dropped to 2, which corresponds to 14 points or 88% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to 13 points or 81% improvement.

Thus, scores on scale items particularly related to impaired concentration and memory were significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat impaired concentration and memory in patients, particularly those suffering from psychotic disorders such as BD.

Thus, according to the present invention, treatment of a patient suffering from cognitive dysfunction reduces or eliminates the cognitive dysfunction. Treatment reduces or eliminates impairment of concentration and memory.

Reduction or elimination of cognitive dysfunction can be reflected at least in improvements in scores for the BDRS items impaired concentration and memory at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the BDRS items concentration and memory impairment) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the BDRS items concentration and memory impairment) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of cognitive dysfunction may be reflected at least in an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the MADRS item Difficulty Concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the MADRS item Difficulty Concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the patient suffers from cognitive dysfunction, improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in cognitive dysfunction, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in cognitive dysfunction (as assessed by at least a "much improved" score on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in cognitive dysfunction (at least reflected by a decrease in the CGI-S score or a score of "much improved" in the CGI-I score or the PGI-I score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As mentioned above, "impaired concentration and memory" is an item of BDRS. Since impaired concentration and memory also affect other aspects of BD, the inventors concluded that the observed improvement in the score of the "difficulty concentrating" item on MADRS will not only bring about a related improvement in the score of the "impaired concentration and memory" BDRS scale item, but also contribute to the overall improvement of the BDRS score.

Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is social/emotional withdrawal or alienation, symptoms of which include anhedonia, emotional withdrawal, and affect loss. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's social/emotional withdrawal or alienation.

Anhedonia (the inability to experience pleasure) has been recognized as a cardinal symptom in bipolar disorder.

Scale items that are particularly relevant to social/emotional withdrawal or alienation are “loss of feeling,” “emotional withdrawal,” and “emotional blunting.” The first item is taken from the MADRS, while the second two items are recorded in the BPRS.

The MADRS item "Anosthesia" represents the subjective experience of reduced interest in one's surroundings or in activities that normally bring pleasure. A reduced ability to respond to situations or people with appropriate emotion.

A score of 0 indicates normal interest in one's surroundings and other people, while a score of 2 indicates a reduced ability to enjoy usual interests. A score of 4 is associated with a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects the experience of emotional paralysis, an inability to feel anger, grief, or pleasure, and a complete or even painful loss of affection for friends and family.

The BPRS item emotional withdrawal relates to the patient's deficits in his or her ability to connect emotionally in the interview situation. Possible scores are:

1- No emotional withdrawal.

2 - Very Mild. Lack of emotional engagement, as evidenced by occasional inability to make reciprocal comments, occasional preoccupied expressions, or an unnatural smile, but mostly interacting spontaneously with the interviewer.

3-Mild. Lack of emotional engagement, as evidenced by an apparent inability to make mutual comments, seeming preoccupied or lacking enthusiasm, but responding when approached by the interviewer.

4 - Moderate. Emotional communication is low in the interview, as the subject does not respond in detail, makes no eye contact, does not seem to care whether the interviewer is listening, or may be preoccupied with psychotic material.

5 - Moderately severe. Same as "4", but no emotional communication during most of the interview.

6 - Severe. Actively avoids emotional engagement. Often fails to respond or responds with yes/no answers (not just due to persecutory delusions). Responds with minimal emotion.

7 - Extreme. Consistently avoids emotional engagement. Does not respond or responds with yes/no answers (not just due to persecutory delusions). May walk away during the interview or simply not respond at all.

The BPRS item affective blunting is associated with a limited range of emotional expression in the face, voice, and gestures as well as apparent apathy or coldness even when discussing painful topics.

Possible ratings are:

1- No emotional blunting.

2 - Very Mild. Slightly suppressed or reserved emotional range, but displays appropriate facial expression and tone of voice within normal limits.

3-Mild. Overall reduced, suppressed or reserved emotional range, without many spontaneous and appropriate emotional responses. Slightly flat tone.

4 - Moderate. The range of emotions is markedly reduced, and except in rare cases, the patient does not show emotion, smile, or respond to distressing topics. The voice is monotonous or spontaneous movements are markedly reduced. After showing emotion or gestures, there is usually a return to emotional apathy.

5 - Moderate to severe. The range of emotions is very small, the patient does not show emotions, smile, or respond to painful topics, and except for very few gestures, facial expressions do not change often. The tone of voice is monotonous most of the time.

6 - Severe. Very little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expressions are static. Tone of voice is monotonous most of the time.

7 - Extreme. There is little emotional range or expression, and the movements are stiff. The tone of voice is always monotonous.

In the study group that received the individualized dosing regimen, the total score for the MADRS item “sensory loss” was 36 at baseline for all eight patients.

After 2 hours, the score dropped to 12, which corresponds to a 24-point or 67% improvement. On day 1 after treatment, the score dropped to 2, which corresponds to a 34-point or 94% improvement. On day 7 after treatment, the score dropped to 6, which corresponds to a 30-point or 83% improvement.

The total score of the BPRS item “emotional withdrawal” was 13 at baseline.

After 3 hours, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On day 1 after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On day 7 after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%.

The total score of the BPRS item “Blunting” was 15 at baseline.

After 3 hours, the score dropped to 11, which corresponds to an improvement of 4 points or 27%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%.

In the 12 mg group, the total score of the MADRS item “sensory loss” was 16 at baseline for all 4 patients.

After 2 hours, the score dropped to 9, which corresponds to an improvement of 7 points or 44%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%. On the seventh day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%.

In the 12 mg group, the total score for the BPRS item “emotional withdrawal” was 13 at baseline.

After 3 hours, the score dropped to 11, which corresponds to an improvement of 2 points or 15%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 7 points or 54%.

In the 12 mg group, the total score for the BPRS item “blunting” was 11 at baseline.

After 3 hours, the score dropped to 8, which corresponds to 3 points or 27% improvement. On the first day after treatment, the score dropped to 6, which corresponds to 5 points or 45% improvement. On the seventh day after treatment, the score dropped to 5, which corresponds to 6 points or 55% improvement.

Thus, the scores of the scale items particularly related to social/emotional withdrawal or alienation, namely the MADRS item "loss of sensation", the BPRS item "emotional withdrawal" and the BPRS item "blunted affect" were significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat social/emotional withdrawal or alienation in patients, especially patients suffering from psychosis (such as BD), i.e., to combat "reduced social participation", "anhedonia" and/or "affective apathy".

Thus, according to the present invention, treatment of a patient suffering from social/emotional withdrawal or alienation reduces or eliminates social/emotional withdrawal or alienation. The treatment reduces or eliminates at least one of anhedonia, emotional withdrawal, and emotional apathy.

Reduction or elimination of social/emotional withdrawal or alienation is reflected in at least an improvement in the score of the BDRS items anhedonia, emotional withdrawal, and/or apathy at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional coldness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional coldness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the MADRS item sensory loss) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the MADRS item sensory loss) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of social/emotional withdrawal or alienation is reflected in at least an improvement in the score of the BPRS item Emotional Withdrawal at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of social/emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item emotional withdrawal) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social/emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item emotional withdrawal) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of social/emotional withdrawal or alienation is reflected in at least an improvement in the score of the BPRS item blunted affect at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of social/emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item blunting) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social/emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item blunting) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the patient suffers from social/emotional withdrawal or alienation, improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in social/emotional withdrawal or detachment, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in social/emotional withdrawal or detachment (as assessed by at least a "much improved" score on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in social/emotional withdrawal or alienation (reflected at least by a decrease in the CGI-S or a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As mentioned above, "reduced social participation", "anhedonia" and "affective blunting" are all items of BDRS. Since social/emotional withdrawal or alienation also affects other aspects of BD, the inventors concluded that the observed improvements in the score of the "loss of sensation" item on MADRS and the scores of "emotional withdrawal" and "affective blunting" on BPRS will not only bring about relevant improvements in the scores of the "reduced social participation", "anhedonia" and/or "affective blunting" BDRS scale items, but also promote the overall improvement of the BDRS score.

Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's suicidal ideation.

In the clinical studies involving 5-MeO-DMT administration mentioned above, the MADRS item “suicidal thoughts” was assessed, among others.

"Suicidal ideation" represents a feeling that life is not worth living, a desire to die naturally, thoughts of suicide, and/or preparations for suicide. A suicide attempt itself should not influence the assessment of this MADRS item.

A score of 0 means the patient enjoys life. If the patient is tired of life and/or has only brief suicidal thoughts, the score is 2. A score of 4 means the patient feels that death would be better, suicidal thoughts are common and suicide is considered a possible solution, but the patient has no specific plan or intention. If the patient has a clear suicide plan and/or is actively preparing for it, the score is 6.

This MADRS item is particularly relevant to suicidal ideation.

In the study group that received the individualized dosing regimen, all eight patients had a total score of 11 for the MADRS item “suicidal thoughts” at baseline.

After 2 hours, the score dropped to 3, which corresponds to an improvement of 8 points or 73%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 10 points or 91%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 8 points or 73%.

In the 12 mg group, the total score of the MADRS item “suicidal thoughts” was 8 at baseline in all 4 patients.

After 2 hours, the score dropped to 3, which corresponds to 5 points or 63% improvement. On the first day after treatment, the score dropped to 5, which corresponds to 3 points or 38% improvement. On the seventh day after treatment, the score dropped to 7, which corresponds to 1 point or 13% improvement.

Thus, the score of the scale item "suicidal thoughts", which is particularly relevant to suicidal ideation, was significantly improved, at least in the patients on the individualized dosing regimen. The inventors conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients, particularly those suffering from psychotic disorders such as BD.

Thus, according to the present invention, treatment of a patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.

Reduction or elimination of suicidal ideation can be reflected at least in an improvement in the score of the BDRS item suicidal ideation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the BDRS item suicidal ideation) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the BDRS item suicidal ideation) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, reduction or elimination of suicidal ideation may be reflected at least in an improvement in the score of the MADRS item suicidal ideation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the MADRS item suicidal ideation) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the MADRS item suicidal ideation) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

If the patient suffers from suicidal ideation, improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in suicidal ideation (as assessed by at least a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in suicidal ideation (as assessed at least by a decrease in the CGI-S score or a score of "much improved" in the CGI-I score or the PGI-I score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As mentioned above, suicidal ideation is an item of the BDRS. Since suicidal ideation also affects other aspects of BD, the inventors concluded that the observed improvement in the score of the "suicidal ideation" item on the MADRS will not only bring about an associated improvement in the score of the "suicidal ideation" BDRS scale item, but also contribute to an overall improvement in the BDRS score.

Another aspect of bipolar disorder (particularly bipolar II disorder) that may be treated by administration of 5-MeO-DMT is episodes with mixed features, in which patients may experience the above-mentioned depressive symptoms, but may also exhibit symptoms such as psychotic symptoms, irritability, lability, increased motor drive, increased verbalization, and agitation. MADRS items associated with these additional symptoms include inner tension (58% improvement observed after 2 hours; 77% improvement on day 1; 54% improvement on day 7 in the IDR cohort; 85% improvement observed after 2 hours; 77% improvement on day 1; 62% improvement on day 7 in the 12 mg cohort) (which may be related to irritability and agitation), pessimistic thoughts (reflected in feelings of guilt or annihilation delusions) (which may be related to psychotic symptoms (reflected in pessimism, guilt, or delusions)), and difficulty concentrating (which may be related to increased verbalization (reflected in distractibility, among other factors)). In addition, the BPRS item guilt may be related to psychotic symptoms, while the BPRS item “tension” (31% improvement after 3 hours and on day 1, and 38% improvement on day 7 observed in the IDR cohort; 36% improvement after 3 hours, and 57% improvement on days 1 and 7 observed in the 12 mg cohort) may be related to irritability and agitation.

Improvement in one or more aspects of BD will also result in overall improvement. Preferably, treatment results in remission.

Relief of depressive symptoms can be reflected by a MADRS score equal to or less than 10 and occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of depressive symptoms can be reflected by a BDRS score equal to or less than 10 and occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Further, alternatively or additionally, relief from depressive symptoms may be reflected by a HAM-D score equal to or less than 7 and occurring no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The present invention particularly provides for the treatment of depression in BD patients without inducing hypomania or mania. Preferably, the treatment of the present invention reduces or eliminates the risk of a patient developing a hypomanic or manic episode.

The risk of treatment-emergent mania or hypomania (TEM) is an important contributing factor to clinical trial design and a significant limiting factor in the treatment of bipolar disorder.

The inventors conclude that treatment with 5-MeO-DMT in accordance with the present invention reduces and/or eliminates the risk of TEM due to several factors related to the compound itself and the manner in which it is administered.

Psychoactive substances reportedly associated with TEM are DMT, ayahuasca (containing DMT and MAO inhibitors), psilocybin, and LSD. These substances induce a psychoactive state that develops over the course of several minutes, lasts for several hours, and is related to the user's level of involvement in the state itself, during which there is ample opportunity for positive and/or negative affective experiences. This extended window of experience provides more opportunity for manic triggering events to occur.

In contrast, 5-MeO-DMT has a rapid onset (only seconds) and usually lasts less than 30 minutes. This provides a brief but intense experience, giving patients a limited window to experience it.

Furthermore, the nature of the psychoactive phase of 5-MeO-DMT is qualitatively different from that reported for the aforementioned psychoactive substances, as it results in a disintegration or loss of self without the feelings of cognitive engagement that accompany the experiences previously associated with the use of TEM-related substances. The inventors conclude that a deep and intense 5-MeO-DMT experience significantly reduces the risk of triggering mania or hypomania.

Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an increased affinity for the 5-HT1A receptor, in which case 5-MeO-DMT acts as a potent agonist, whereas the effects of these other compounds are primarily mediated through 5-HT2A agonism. 5-HT1A agonists have been reported to reduce impulsivity and aggression, while 5-HT2A agonists cause short-term increases in these same traits (Carhart-Harris and Nutt 2017). Additionally, the dopamine system has been implicated in causing mania (Chen 201 0), and increases in dopamine drive have been associated with mania (Berk 2007). LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT (Ray, 2019).

Furthermore, reports of TEM associated with the use of psychoactive substances appear to indicate the use of a wide range of the corresponding compounds (e.g., DMT/ayahuasca, psilocybin, LSD).

The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

Further, antidepressants have been reported to induce isolated hypomanic episodes in patients with treatment-resistant depression (TRD) (Bader, Cynthia D. and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of induction of hypomania.

The same clinical trial showed that sleep reduction significantly improved MADRS scores, while episodes of (hypo)mania are reportedly triggered by factors such as sleep reduction (Pancheri, 2019).

Thus, when treated according to the present invention, patients do not experience treatment-induced mania or hypomania.

The Young Mania Rating Scale (YMRS) can be used to assess the occurrence of treatment-induced mania or hypomania. Treatment-induced mania or hypomania is considered to be avoided if the patient's Young Mania Rating Scale (YMRS) total score is less than or equal to 15, preferably less than or equal to 12, assessed about 2 hours; 1 day; 7 days; 14 days and/or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Mode of administration

The therapeutically effective amount of 5-MeO-DMT is administered by inhalation, by nasal administration, by buccal administration, or by sublingual administration. Administration via these routes can ensure rapid onset of action. The most preferred route of administration is by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration formulation, examples of which are known in the art. For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably the hydrobromide salt) or in the form of a formulation of a pharmaceutically acceptable salt (preferably the hydrobromide salt). Examples of suitable devices are known in the art.

Buccal or sublingual administration may also rely on a pharmaceutically acceptable salt of 5-MeO-DMT, preferably the hydrobromide salt, itself or in the form of a formulation, such as a tablet, film, spray, cream, as is known in the art.

Administration is particularly carried out by inhalation of an aerosol. This aerosol comprises (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg/1 to about 18 mg/l, such as about 0.5 mg/l to about 12.5 mg/l, preferably about 1.3 mg/l to about 10 mg/l, in particular about 2 mg/l to about 9 mg/l. The pharmaceutically acceptable gas is preferably air.

The aerosol particles preferably contain less than 1% by weight of impurities, in particular less than 0.5% by weight of impurities. In addition, they preferably contain less than 0.5% by weight of 5-MeO-DMT degradation products, in particular less than 0.2% by weight of 5-MeO-DMT degradation products, which are produced by chemical modifications of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

In a further preferred aspect, the aerosol consists essentially of: (a) air; (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The aerosol particles preferably contain 5-MeO-DMT in the free base form.

The aerosol is preferably characterised by having a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular less than 2 μm and greater than 0.1 μm.

The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer of 5-MeO-DMT to generate aerosol particles. The thin layer can have a thickness of less than about 10 μm, particularly less than about 7.5 μm. The thin layer can have a thickness in the range of about 0.1 μm to about 10 μm, particularly in the range of about 0.3 μm to about 7.5 μm.

A thin layer of 5-MeO-DMT disposed on a solid support can be exposed to thermal energy via air passing through the thin layer. Alternatively, a thin layer of 5-MeO-DMT disposed on a solid support can be exposed to thermal energy via the solid support.

The air passing through the thin layer may have a temperature in the range of about 180° C. to about 260° C. The air passing through the thin layer may specifically have a temperature of about 210° C. and pass through the thin layer at a rate of about 12 1/min for about 15 seconds.

The aerosol particles may be contained in a volume equal to or less than about 3 liters, in particular contained in a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. Delivery to the patient is preferably via a single inhalation.

5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharmaceutically acceptable salt thereof are provided in the form of an aerosol. These aerosols have a suitable aerosol particle mass density so that a therapeutically effective dose of the aerosol can be administered to a patient via a single inhalation.

Aerosols that can be used in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is difficult to predict which conditions are suitable for safe, efficient and predictable aerosolization, particularly when the aerosol is to be used for systemic delivery of the compound to a patient via the lungs. The relevant variables in this context include a) the dosage of the compound, b) the morphological state (e.g., crystalline form or thin layer form) of the compound that can be used for aerosolization, c) the amount of thermal energy to which the compound is exposed (defined by temperature and exposure duration) and d) the volume (defined by flow rate and airflow duration) of the air introduced to form the aerosol.

The compositions and methods described herein are used to safely, efficiently, and predictably deliver 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient systemically by inhalation. "Safe" means that the aerosol particles should contain only minimal amounts of impurities and 5-MeO-DMT degradation products, "efficient" means that the dose is aerosolized to a specified extent, preferably almost completely aerosolized or completely aerosolized, i.e., the aerosol has the desired physical properties so that the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is delivered systemically via the lungs primarily via absorption in the alveoli, and the patient can inhale the aerosol in a single inhalation (i.e., within one deep breath), and "predictable" means that there is little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

A suitable aerosol can be achieved by a) providing a therapeutically effective amount of 5-MeO-DMT in the form of a thin layer on a solid support, b) exposing the thin layer of 5-MeO-DMT to an elevated controlled temperature for a short period of time, and c) providing a controlled amount of air such that an aerosol is formed.

A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by: a) exposing a thin layer of 5-MeO-DMT disposed on a solid support to thermal energy, and b) passing air through the thin layer of 5-MeO-DMT; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% by weight impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) it can be delivered to a patient via a single inhalation.

An aerosol volume deliverable to a patient via a single inhalation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, less than 1 weight % impurities, and less than 0.5 weight % 5-MeO-DMT drug degradation products can be generated by defining: a) the dose of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by the temperature and the duration of exposure), and d) the total amount of air that passes through the thin layer of 5-MeO-DMT (defined by the airflow rate and the duration of airflow].

Preferably, the 5-MeO-DMT thin layer is exposed to thermal energy via air passing through the thin layer, in which case the air is heated. The heated air passing through the thin layer may have a temperature in the range of about 180° C. to about 260° C. The air passing through the thin layer may particularly have a temperature of about 210° C.

Alternatively, the thin layer of 5-MeO-DMT is exposed to thermal energy via a solid support, in which case the air passing through the thin layer is not heated, but the solid support is heated. The heated solid support may have a temperature in the range of about 180°C to about 420°C.

Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is of high purity, at least 99%, preferably at least 99.5%.

Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT disposed on the solid support is from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, and more preferably from about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

The solid support on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided can have a variety of shapes. Examples of such shapes include, but are not limited to, cylinders having a diameter less than 1.0 mm, boxes having a thickness less than 1.0 mm, and nearly any shape filled with small holes (e.g., less than 1.0 mm in size). Preferably, the solid support provides a large surface area to volume ratio (e.g., greater than 100/meter) and a large surface area to mass ratio (e.g., greater than 1 ^cm2 /gram).

A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet with a thickness of 0.25 mm has a surface area to volume ratio of about 8,000/meter. Rolling the sheet into a hollow cylinder with a diameter of 1 cm produces a support that retains the high surface area to mass ratio of the original sheet, but has a lower surface area to volume ratio (about 400/meter).

A variety of different materials are used to construct the solid support. Classes of such materials include, but are not limited to, metals, inorganic materials, carbonaceous materials, and polymers. The following are examples of material classes: aluminum, silver, gold, stainless steel, copper, and tungsten; silicon dioxide, glass, silicon, and aluminum oxide; graphite, porous carbon, carbon yarn, and carbon felt; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coating variations of materials may also be used.

When aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina with a defined surface area greater than 2 ^m2 /g from Aldrich, St. Louis, Mo.), and silicon wafers used in the semiconductor industry. Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

Preferably, the thickness of the 5-MeO-DMT layer disposed on the solid support is less than about 10 μm, in particular less than about 7.5 μm. The layer may have a thickness in the range of about 0.1 μm to about 10 μm, in particular in the range of 0.3 μm to 7.5 μm.

Preferably, the total amount of air passing through the 5-MeO-DMT thin layer is limited to about 6 liters/minute to about 40 liters/minute, preferably about 8 liters/minute to about 16 liters/minute of flow velocity, and the duration of the air flow is selected so that the cumulative volume of the aerosol is no more than about 3 liters, preferably about 1 liter to 3 liters, such as 2 liters to 3 liters.For example, when the air flow rate is about 6 liters/minute, the air flow duration should be less than about 30 seconds.A useful specific air flow rate and duration are about 12 liters/minute and about 15 seconds, thereby produce about 3 liters of aerosol volume.Another useful specific air flow rate and duration are 10 liters/minute and about 15 seconds, thereby produce about 2.5 liters of aerosol volume.Another useful specific air flow rate and duration are 8 liters/minute and about 15 seconds, thereby produce about 2 liters of aerosol volume.Another useful specific air flow rate and duration are 10 liters/minute and about 12 seconds, thereby produce about 2 liters of aerosol volume.

The aerosol formation rate is greater than 0.1 mg/second.

The aerosol has an aerosol particle mass density of about 0.5 mg/l to about 18 mg/l, such as about 0.5 mg/l to about 12.5 mg/l, preferably about 1.3 mg/l to about 10 mg/l, in particular about 2 mg/l to about 9 mg/l.

The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and greater than 0.1 microns, preferably less than 2.5 microns and greater than 0.1 microns, most preferably less than 2 microns and greater than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% by weight impurities, preferably less than 0.5% by weight impurities.

The 5-MeO-DMT aerosol particles are characterized by less than 0.5 wt % 5-MeO-DMT degradation products, preferably less than 0.2 wt % 5-MeO-DMT degradation products.

A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by: a) exposing a 12 mg dose of 5-MeO-DMT configured as a thin layer less than 5 microns thick on a solid support to a temperature of 210° C. for 15 seconds by passing heated air through the thin layer; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% impurities and less than 0.5% by weight of 5-MeO-DMT degradation products, and 3) it can be delivered to a patient via a single inhalation.

Those skilled in the art who understand the aerosol properties and aerosolization conditions defined in the present invention can determine suitable gasification devices or systems, which result in desired aerosol properties. Examples of such suitable gasification devices or systems include, for example, Volcano Medic gasification systems (Storz & Bickel, Germany) with associated dosing capsules with a drip pad; disclosed in, for example, EP 0 933 093 B1 and EP 1 884 254 B1 and registered community design 003387299-0001) and Staccato devices (Alexza Pharmaceuticals, Mountain View, USA; disclosed in, for example, US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2). The generated aerosol can be collected in the balloon and inhaled from the balloon by the patient.

Dosage regimen

The present invention also provides dosage ranges, specific dosages, and dosing regimens (administration regimens).

The present invention is based in part on the inventors' conclusion that peak psychedelic experiences occur during the acute phase following administration of 5-MeO-DMT, which drives the therapeutic benefits of 5-MeO-DMT in patients suffering from BD (particularly one or more of the aspects defined above), either causally or at least as a surrogate behavioral marker of a potential unknown therapeutic mechanism.

Therefore, achieving peak experience more quickly in a greater proportion of patients and with better reproducibility in individual patients will lead to a better therapeutic profile than with previously tested psychedelics and dosing regimens.

Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., the absence of waning or loss of psychedelic effects upon re-administration) as a basis for enabling a dosing regimen of frequent re-administration (such as more than once daily or once daily) designed to increase the incidence of peak experiences, thereby increasing therapeutic benefit. Such repeated administrations over a short period of time also allow for intra-individual dose optimization, which reduces the risk of overdose, which may otherwise result in physical side effects such as serotonin syndrome, negative psychotic reactions (such as flashbacks of the experience at a later time point), induction of mania or hypomania, or less meaningful psychedelic experiences with little or no memory of the altered state (so-called "whiteouts"). Furthermore, starting with a low dose allows the patient to become familiar with the general psychedelic experience and allows for preparation for the more intense symptoms that occur at higher doses, which will have a positive impact on the experience at the higher doses. Furthermore, the prospect of being able to begin treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the repeatability of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be possible with other psychedelics due to the late onset and prolonged duration of psychedelic effects and the rapid development of tolerance (i.e., diminished or absent psychedelic effects following re-administration) that may persist for several days.

Patients diagnosed with bipolar disorder, particularly bipolar disorder type II, particularly with a current major depressive episode (including treatment-resistant forms of these disorders, and including these disorders associated with suicidal ideation) as defined herein are treated by administering 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy, i.e., the patient is not receiving any other treatment for BD or symptoms associated with BD.

The dosage of 5-MeO-DMT administered to patients diagnosed with bipolar disorder, particularly bipolar disorder type II, particularly suffering from a current major depressive episode (including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation) as defined herein is in the range of about 1 mg to about 25 mg, or any amount within the range, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also receive an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. Please note that in this specification, when a range is listed (such as "about 1 mg to about 25 mg"), the inventors consider all discrete values within the range, some of which are explicitly mentioned, but not all of them - this is only for the purpose of brevity.

In preferred embodiments, improved methods of treating patients diagnosed with bipolar disorder, particularly bipolar disorder type II, particularly suffering from a current major depressive episode, as defined herein, including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT comprises the onset of a clinical response no later than about 2 hours after administration of the 5-MeO-DMT.

In preferred embodiments, improved methods of treating patients diagnosed with bipolar disorder, particularly bipolar disorder type II, and particularly suffering from a current major depressive episode, as defined herein, including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT include a sustained clinical response, including a clinical response that occurs no later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

In a preferred embodiment, improved methods of treating patients diagnosed with bipolar disorder, particularly bipolar disorder type II, as defined herein, particularly suffering from a current major depressive episode (including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprise administering more than a single dose of 5-MeO-DMT.

In a preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 1 to 4 hours, preferably 1 to 2 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

In an embodiment, the dose of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg at the first administration within each treatment block and then increased with each subsequent administration within each treatment block until 20 mg is reached, or all administrations within that treatment block have been administered, whichever is earlier.

In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg at the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: 20 mg is reached, or all administrations within that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects.

For embodiments where the dose of a subsequent administration is increased, the dose of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg to the dose of the previous administration. For example, if the first administered dose is 6 mg and the dose increase is 6 mg, the second administered dose is 12 mg unless one of the aforementioned stopping criteria has been met. Preferably, the third administered dose is 18 mg.

In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg at the first administration, and then increased to a dose selected from about 8 mg to about 14 mg at the second administration, and to a dose selected from about 14 mg to about 20 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in a first treatment block is selected from about 2 mg to about 8 mg, and then increased with each subsequent administration within the first treatment block until the earlier of: reaching 20 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 18 mg, because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks is 18 mg.

In a most preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 2 mg to about 8 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 8 mg to about 14 mg, and the third administration in the first treatment block will be increased to a dose selected from about 14 mg to about 20 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

It will be appreciated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens and that the appropriate weight of the salt to be administered may be calculated based on the specified weight of the free base, assuming equimolar amounts are used.

According to the present invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

Patients can be identified as having a "peak psychedelic experience" by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

Patients experiencing a “peak psychedelic experience” can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Nothingness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

According to the present invention, whether a patient has a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 points in the Peak Experience Scale (PES), which is also called the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient's responses from 0 to 100 to the following three questions: 1. How intense was the experience; 2. How much loss of control was there; 3. How significant (i.e., profound and important) was the experience?

Aspects of the Invention

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient diagnosed with bipolar disorder.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 1, wherein the patient is diagnosed with bipolar disorder type II.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 1, wherein the patient is diagnosed with bipolar disorder type I.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 3, wherein the patient suffers from a current major depressive episode.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 4, wherein the patient has a total score of Montgomery-Asberg Depression Rating Scale (MADRS) equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 4 or aspect 5, wherein the patient has a Bipolar Depression Rating Scale (BDRS) total score equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not achieved adequate improvement after at least two adequate courses of treatment.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of treatment, wherein at least one of the two courses is drug therapy.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of medication.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 9, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 8.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 10, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 11, wherein a dose of about 4 mg to about 20 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 11, wherein a dose of about 6 mg, about 12 mg or about 18 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 12, wherein the 5-MeO-DMT or a salt thereof is administered at a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a higher dose than the previous administration unless the patient experiences a peak psychedelic experience.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 14, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 8 mg for the first administration, then increased to a dose of about 8 mg to about 14 mg for the second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 14 mg to about 20 mg for the third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 15, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 14 to 16, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 11 to 17, wherein the occurrence of a peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Ocean-like Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 18, wherein the occurrence of a peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any of the preceding aspects, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via inhalation, or by nasal, buccal or sublingual administration.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 20, wherein 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol, the aerosol comprising (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg/l to about 18 mg/l, such as to about 12.5 mg/l.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 21, wherein the aerosol is generated by: a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer to generate aerosol particles.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 20 to 22, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled via a single breath.

24. 5-MeO-DMT for use as described in aspects 20 to 23, wherein the 5-MeO-DMT is used in the form of a free base.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 24, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 25, wherein a clinical response is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 26, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 27, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 28, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 29, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 50% improvement in BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 30, wherein relief of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 31, wherein a clinical response is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 50% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 32, wherein relief of depressive symptoms is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 33, wherein the clinical response, as reflected by at least a 50% improvement in BDRS, MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 34, wherein there is a clinical response on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 75% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 35, wherein on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the patient's depressive symptoms are alleviated, and the alleviation is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 36, wherein the clinical response, as reflected by at least a 50% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 37, wherein there is a clinical response on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 75% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 38, wherein on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the patient's depressive symptoms are alleviated, and the alleviation is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7.

40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 39, wherein the clinical response, as reflected by at least a 50% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 40, wherein there is a clinical response on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 75% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 41, wherein on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the patient's depressive symptoms are alleviated, and the alleviation is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7.

43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 42, wherein the patient does not experience treatment-induced mania or hypomania.

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 43, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 44, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

46. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 45, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 46, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 47, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 48, wherein the treatment results in improvement of at least one of sleep disturbance, psychomotor retardation, negative thinking, anxiety, cognitive dysfunction, and social/emotional withdrawal or alienation.

50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 49, wherein the patient suffers from a sleep disorder and the treatment reduces or eliminates the sleep disorder.

51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the patient suffers from insomnia and the treatment reduces or eliminates the insomnia.

52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the patient suffers from excessive sleep and the treatment reduces or eliminates the excessive sleep.

53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 to 52, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

54. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 to 53, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 to 54, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 to 55, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein said reduction or elimination of sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS item sleep disturbance.

58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 57, wherein said reduction or elimination of sleep disturbances lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 57, wherein said reduction or elimination of sleep disturbances lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 57, wherein said reduction or elimination of sleep disturbances persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score of the MADRS item sleep loss on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 50 or 61, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 50, 61 or 62, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 or 61 to 63, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the reduction or elimination is reflected in an improvement in the score of the MADRS item sleep loss.

66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 65, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 65, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 65, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 50 or 69, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 50, 69 or 70, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 or 69 to 71, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 73, wherein the improvement in sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 73, wherein the improvement in sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 73, wherein the improvement in sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on the 1st day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example about 24 hours, wherein the recall period spans from the time point at which the acute psychedelic experience resolves after the last dose to the assessment time point.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49 or 77, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last dose to the assessment time point.

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49, 77 or 78, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last dose to the assessment time point.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49 or 77 to 79, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last dose to the assessment time point.

81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 50, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience subsided after the last administration to the assessment time point.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience resolves after the last administration to the assessment time point.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last administration to the assessment time point.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last administration to the assessment time point.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 84, wherein the patient suffers from psychomotor retardation and the treatment reduces or eliminates the psychomotor retardation.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 85, wherein the treatment improves or eliminates decreased energy and activity and/or decreased motivation.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85 or 86, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

88. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 to 87, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

89. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 to 88, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

90. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 to 89, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

91. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 to 90, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

92. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85 or 86, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 92, wherein said reduction or elimination of psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 92, wherein said reduction or elimination of psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 92, wherein said reduction or elimination of psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 85, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazyness about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

97. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85 or 96, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazyness on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

98. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85, 96 or 97, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

99. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 or 96 to 98, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

100. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 85 or 96 to 99, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

101. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 85, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 101, wherein said reduction or elimination of psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 101, wherein said reduction or elimination of psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

104. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 101, wherein said reduction or elimination of psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 85, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85 or 105, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85, 105 or 106, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 or 105 to 107, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

109. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 or 105 to 108, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

110. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 84, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 110, wherein the improvement in psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 110, wherein the improvement in psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

113. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 110, wherein the improvement in psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

114. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 113, wherein the patient suffers from negative thoughts and the treatment reduces or eliminates the negative thoughts.

115. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 114, wherein the treatment reduces or eliminates feelings of worthlessness, helplessness and hopelessness and/or guilt.

116. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BDRS items worthlessness, helplessness and hopelessness and/or guilt about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

117. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114 to 116, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BDRS items worthlessness, helplessness and hopelessness and/or guilt on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

118. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114 to 117, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness, helplessness and hopelessness and/or guilt on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

119. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114 to 118, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness, helplessness and hopelessness and/or guilt on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

120. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114 to 119, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BDRS items worthlessness, helplessness and hopelessness and/or guilt on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

121. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness, helplessness and hopelessness and/or guilt.

122. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 121, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness, helplessness and hopelessness and/or guilt.

123. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 121, wherein said reduction or elimination of negative thoughts lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness, helplessness and hopelessness and/or guilt.

124. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 121, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness, helplessness and hopelessness and/or guilt.

125. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114 to 115, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

126. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 125, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

127. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115, 125 or 126, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

128. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 125 to 127, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

129. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 125 to 128, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

130. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

131. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 130, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

132. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 130, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

133. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 130, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

134. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

135. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 134, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

136. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115, 134 or 135, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

137. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 134 to 136, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

138. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 134 to 137, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

139. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item guilt.

140. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 139, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

141. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 139, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

142. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 139, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

143. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

144. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 143, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

145. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115, 143 or 144, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

146. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 143 to 145, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

147. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114, 115 or 143 to 146, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

148. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 113, wherein the patient suffers from negative thinking and improvement in negative thinking occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

149. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 148, wherein said improvement in negative thinking persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

150. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 148, wherein said improvement in negative thinking persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

151. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 148, wherein said improvement in negative thinking persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

152. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 151, wherein the patient suffers from anxiety and the treatment reduces or eliminates the anxiety.

153. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

154. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 152 or 153, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

155. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 152 to 154, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

156. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 152 to 155, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

157. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 152 to 156, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

158. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein said reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item anxiety.

159. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 158, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

160. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 158, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

161. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 158, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

162. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

163. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 152 or 162, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

164. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 152, 162 or 163, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

165. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 152 or 162 to 164, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

166. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 152 or 162 to 165, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

167. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein said reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item anxiety.

168. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 167, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item Anxiety.

169. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 167, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item anxiety.

170. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 167, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item Anxiety.

171. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

172. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 152 or 171, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

173. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 152, 171 or 172, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

174. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 152 or 171 to 173, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

175. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 152 or 171 to 174, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

176. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 151, wherein the patient suffers from anxiety and improvement in anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

177. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 176, wherein the improvement in anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

178. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 176, wherein the improvement in anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

179. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 176, wherein the improvement in anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

180. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 179, wherein the patient suffers from cognitive dysfunction and the treatment reduces or eliminates the cognitive dysfunction.

181. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 180, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

182. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 180 or 181, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

183. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180 to 182, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

184. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180 to 183, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

185. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180 to 184, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

186. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 180, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items concentration and memory impairment.

187. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 186, wherein said reduction or elimination of cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items concentration and memory impairment.

188. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 186, wherein said reduction or elimination of cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

189. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 186, wherein said reduction or elimination of cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

190. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 180, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

191. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 180 or 190, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

192. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180, 190 or 191, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

193. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180 or 190 to 192, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

194. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180 or 190 to 193, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

195. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 180, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

196. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 195, wherein said reduction or elimination of cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

197. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 195, wherein said reduction or elimination of cognitive dysfunction persists until at least 1 to 4 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

198. 5-MeO--DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 195, wherein said reduction or elimination of cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

199. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 180, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

200. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 180 or 199, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

201. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180, 199 or 200, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

202. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180 or 199 to 201, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

203. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 180 or 199 to 202, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

204. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 179, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

205. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 204, wherein the improvement in cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

206. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 204, wherein the improvement in cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

207. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 204, wherein the improvement in cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

208. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 207, wherein the patient suffers from social/emotional withdrawal or alienation, and the treatment reduces or eliminates the social/emotional withdrawal or alienation.

209. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 208, wherein the treatment reduces or eliminates at least one of anhedonia, emotional withdrawal, and emotional apathy.

210. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

211. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208 to 210, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or apathy at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

212. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208 to 211, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

213. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208 to 212, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

214. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208 to 213, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

215. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or emotional apathy.

216. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 215, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or emotional apathy.

21 7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 21 5, wherein said reduction or elimination of social/emotional withdrawal or alienation lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or emotional apathy.

218. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 215, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or emotional apathy.

219. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

220. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 219, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

221. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209, 219 or 220, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

222. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 219 to 221, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score for the MADRS item sensory loss on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

223. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 219 to 222, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score for the MADRS item sensory loss on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

224. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item sensory loss.

225. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 224, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

226. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 224, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

227. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 224, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

228. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

229. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 228, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

230. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209, 228 or 229, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

231. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 228 to 230, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

232. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 228 to 231, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

233. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item emotional withdrawal.

234. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 233, wherein said reduction or elimination of social/emotional withdrawal or alienation lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

235. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 233, wherein said reduction or elimination of social/emotional withdrawal or alienation lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

236. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 233, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

237. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

238. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 237, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item blunted affect at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

239. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209, 237 or 238, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item blunting on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

240. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 237 to 239, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

241. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 237 to 240, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

242. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item blunted affect.

243. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 242, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

244. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 242, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

245. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 242, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

246. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

247. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 246, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

248. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209, 246 or 247, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

249. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 246 to 248, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

250. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 246 to 249, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

251. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 207, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

252. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

253. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social/emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

254. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

255. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 254, wherein the treatment reduces or eliminates suicidal ideation.

256. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

257. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 255 or 256, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

258. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 to 257, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

259. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 to 258, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

260. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 to 259, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

261. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS item suicidal ideation.

262. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 261, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

263. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 261, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

264. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 261, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

265. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item Suicidal Thoughts about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

266. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 255 or 265, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

267. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255, 265 or 266, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

268. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 or 265 to 267, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

269. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 or 265 to 268, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

270. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item Suicidal Thoughts.

271. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 270, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

272. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 270, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

273. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 270, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

274. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

275. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 255 or 274, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

276. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 255, 274 or 275, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

277. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 or 274 to 276, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

278. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 or 274 to 277, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

279. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 254, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

280. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 279, wherein the improvement in suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

281. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 279, wherein the improvement in suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

282. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 279, wherein the improvement in suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

283. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 282, wherein the treatment reduces or eliminates at least one of psychotic symptoms, irritability, instability, increased motor drive, increased speech, and agitation.

Example

The following examples are set forth to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit the invention described in the claims that follow in any manner.

Example 1-5 - MeO-DMT Aerosol Generation and Administration

Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask so that a 200 μl solution volume contains the target dose of 5-MeO-DMT free base to be administered to the volunteer or patient via inhalation. A typical target dose is 1 mg to 25 mg 5-MeO-DMT. For example, for a target dose of 18 mg 5-MeO-DMT, dissolve 90 mg of 5-MeO-DMT in 100% ethanol in a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

Step 2: 200 μl of the solution was transferred into a dosing capsule (Storz & Bickel, Germany) containing a drip pad and then the lid of the dosing capsule was closed.

Step 3: The dosing capsules filled with the 5-MeO-DMT ethanol solution were transferred to the filling chamber of the first Volcano Medic vaporizer, which was preheated and set to 55°C. The gas flow of the vaporizer was then turned on for 60 seconds at a preset rate of approximately 12 l/min. The heated air would flow through the dosing capsules, allowing the ethanol to evaporate, while the target dose of 5-MeO-DMT remained in the capsules as a thin layer covering the stainless steel mesh. The accurate preparation of the dosing capsules was confirmed by demonstrating that the final weight gain of the capsules was approximately equal to the target dose of 5-MeO-DMT compared to the empty capsule weight.

Step 4: The prepared dosing capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second VolcanoMedic vaporizer, which has been preheated and set to 210°C with the airflow turned on for at least 5 minutes and then turned off immediately before transfer. A valved inhalation balloon (Storz & Bickel, Germany) is mounted on the socket of the filling chamber, the filling chamber is tightly closed, and the airflow is immediately turned on at a preset flow rate of approximately 12 1/min for 15 seconds and then turned off. This will allow the entire dose of 5-MeO-DMT to be aerosolized and distributed in the approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of 5-MeO-DMT can be confirmed by demonstrating that the capsule weight has returned to approximately its initial weight.

Step 5: The balloon is then disconnected from the filling chamber, which automatically closes the valve. After the mouthpiece is connected to the balloon, the aerosol is ready to be immediately administered to the volunteer or patient.

Step 6: To prepare for administration, ask the patient to first take 1-2 deep breaths, exhale completely, and end the process with a deep exhalation. Then, hold the mouthpiece firmly against the lips, inhale the entire volume of the balloon in one breath, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020/169850A1, the contents of which are incorporated herein by reference.

Example 2 - Preparation of High Purity 5-MeO-DMT

5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 volumes) at 35 to 40 ° C and then cooled to room temperature within 30 minutes. After stirring at room temperature for 50 minutes, no crystallization was observed, so the batch temperature was reduced to 7 to 12 ° C within 30 minutes. Crystallization occurred after stirring at 7 to 12 ° C for 10 minutes. It was then stirred at 7 to 12 ° C for 1 hour, and the batch was subsequently filtered. After washing with MTBE (1 mL, 0.5 volumes) at 7 to 12 ° C, the batch was dried under vacuum for 3.5 hours to obtain 1.02 g of light orange solid (50% recovery). As described in WO 2020/169850 A1, the purity of the separated solid was analyzed by HPLC. The purity is 99.74% area.

The analytical results further indicated that the level of individual impurities was less than 0.10% area. Solvent analysis of the sample indicated MTBE level was 17 ppm.

Example 3-5-Preparation of MeO-DMT Hydrobromide

5-MeO-DMT HBr was prepared on a 100 mg scale.

5-MeO-DMT free base was combined with isopropyl acetate (10 vol) and the resulting 5-MeO-DMT solution was heated to 50° C. HBr (1 M in ethanol, 1 eq) was charged in a single aliquot. The mixture was maintained at this temperature and equilibrated for 3 hours.

After 1 hour, a suspension was formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried in vacuo at 40°C for 18 hours.

An off-white crystalline material was obtained.

The salt has a melting point of 174°C and is characterized in that it has an X-ray diffraction pattern comprising peaks at 14.5°2·±0.2°2·; 16.7°2·±0.2°2·; 17.0°2·±0.2°2·; 20.6°2·±0.2°2·; 20.7°2·±0.2°2·; 21.4°2·±0.2°2·; 24.2°2·±0.2°2·; 24.8°2·±0.2°2·; 25.3°2·±0.2°2·; 27.4°2·±0.2°2·; which is measured using Cu K· radiation.

Example 4 - Determination of Inhibition Constants of Central 5-HT1A and 5-HT2A Receptors in Postmortem Human Brain Membranes Preparations

In the present study, the affinity of three psychedelic test compounds (psilocybin dephosphate, DMT, and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue (from the hippocampus and frontal cortex, respectively) was determined using radioligand binding techniques.

Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors died suddenly, had no history of coma, psychiatric or neurological disease, were under 65 years old, and had a postmortem interval of less than or equal to 72 hours.

Binding to 5-HT1A receptors in postmortem human hippocampus

The hippocampus was homogenized in ice-cold 0.25M sucrose (1:30 weight/volume) using an electric Teflon pestle (12 times at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 minutes. The supernatant was stored on ice, and the pellet was homogenized again in 0.25M sucrose (1:15 weight/volume) and centrifuged at 750 g for 10 minutes. The supernatants were combined and diluted with ice-cold membrane preparation buffer (1:100 weight/volume), using a tightly fitting glass/Teflon homogenizer (12 times, 800 rpm), and centrifuged at 20,500 g for 10 minutes. The pellet was resuspended in ice-cold membrane preparation buffer and incubated at 37°C for 10 minutes, then centrifuged at 20,500 g for 10 minutes. The pellet was resuspended and centrifuged for the last time to wash the tissue (20,500 x g, 10 minutes). The resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equal to 3.125 mg tissue wet weight/ml. All centrifugations were performed at 4°C. The membrane preparation buffer consisted of 50 mM Tris-HCl, pH 7.7, 4 mM CaCl ₂ , and 0.1% ascorbic acid. The assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCl ₂ , 0.1% ascorbic acid, and 10 μM Pargyline.

For saturation binding analysis, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue/tube) were incubated with 50 μl 0.075-9.6 nM [ ³ H]8-OH-DPAT and either 50 μl assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding) for 30 min at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

In the displacement assay, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue/tube) were incubated with 50 μl 0.6 nM [ ³ H]8-OH-DPAT and either 50 μl assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding) or 50 μl of one of ten concentrations of test compound between 1 and 10000 nM for 30 min at 25°C.

Membrane-bound radioactivity was recovered by vacuum filtration through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. The filters were quickly washed with ice-cold wash buffer (wash settings 0, 9, 9) and radioactivity was determined by liquid scintillation counting (1 ml Packard MV Gold scintillation counter).

Nonlinear regression was used to calculate the compound concentration required to inhibit 50% of specific binding ( _IC50 ) and the Hill slope.K1 was calculated using a one-site binding _model allowing for ligand depletion.

Binding to 5-HT2A receptors in postmortem human frontal cortex

The frontal cortex was homogenized in ice-cold 0.25M sucrose (1:30 weight/volume) using an electric Teflon pestle (12 times at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 minutes. The supernatant was stored on ice, and the pellet was homogenized again in 0.25M sucrose (1:15 weight/volume) and centrifuged at 750 g for 10 minutes. The supernatants were combined and diluted with ice-cold 50 mM Tris-HCl assay buffer, pH 7.4 (1:100 weight/volume), homogenized using a tightly fitting glass/Teflon homogenizer (12 times, 800 rpm), and centrifuged at 20,500 g for 10 minutes. The pellet was further centrifuged twice to wash the tissue (20,500 x g, 10 minutes). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, with a tissue concentration equal to 10 mg tissue wet weight/ml. All centrifugations were performed at 4°C.

For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg tissue wet weight/tube) were incubated with 50 μl 0.00625-0.8 nM [ ³ H]MDL-100,907 and 50 μl assay buffer or 50 μl 10 μM ketanserin (nonspecific binding) for 60 min at 25° C. Assay and wash buffers consisted of 50 mM Tris-HCl buffer, pH 7.4.

In the displacement assay, frontal cortex membranes (400 μl; equivalent to 4 mg wet weight tissue/tube) were incubated with 50 μl of 0.1 nM [3H]MDL-100,907 and either 50 μl of assay buffer (total binding) or 50 μl of 10 μM ketanserin (nonspecific binding) or 50 μl of one of ten concentrations of test compound between 1 and 10000 nM for 60 min at 25°C.

Membrane-bound radioactivity was recovered and determined as described above. Data analysis was also performed as described above.

result

The dissociation constants (K _d values) of [ ³ H]8-OH-DPAT and 5-HT1A receptors in the hippocampal membrane of postmortem human brain tissue from three donors were determined. The dissociation constants (K _d values) obtained were 0.51, 0.28, and 0.52 nM, respectively.

The average inhibition constants ( _Ki values) for dephosphopsilocybin, DMT, and 5-MeO-DMT were 48, 38, and 1.80 nM, respectively (average n=3). The Hill slopes for all compounds were close to unity, indicating a single-site binding model.

The dissociation constants (K _d values) of [ ³ H]MDL-100,907 and 5-HT2A receptors in the frontal cortex membranes of postmortem human brain tissue from three donors were determined. The dissociation constants (K _d values) obtained were 0.11, 0.08, and 0.08 nM, respectively.

The average inhibition constants ( _Ki values) for dephosphopsilocybin, DMT, and 5-MeO-DMT were 37, 117, and 122 nM, respectively (average n=3). The Hill slopes for all compounds were close to unity, indicating a single-site binding model.

The selectivity ratios of dephosphorylated psilocybin, DMT, and 5-MeO-DMT for 5-HT2A receptors over 5-HT1A receptors are 0.78, 3.1, and 68, respectively.

Example 5 - Clinical Trial in Patients Suffering from TRD

A Phase 1/2 clinical trial of 5-MeO-DMT administered via inhalation as described herein has been completed in patients with treatment-resistant major depressive disorder (TRD). This trial is designed in two parts. Part A is an open-label, single-arm, single-dose Phase 1 trial with two dose levels (12 mg (n=4) and 18 mg (n=4)). Part B is an open-label, single-arm Phase 2 trial with an individualized dosing regimen and a step-wise increase in the 5-MeO-DMT dose within the patient. Patients (n=8) receive at least one and up to three doses of 5-MeO-DMT (6 mg, 12 mg, and 18 mg) per day, with higher doses only being administered when the previously administered dose does not achieve a peak experience. The primary endpoint of Part A is to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in TRD patients. The primary endpoint of Part B is to evaluate the effect on depression severity, as assessed by the proportion of patients who are relieved on the seventh day after administration, with relief defined as a total MADRS score of less than or equal to 10.

In Part A, 3 of 4 patients in both groups (12 mg and 18 mg) experienced at least one ADR, all of which were mild and resolved spontaneously. No SAEs were reported.

Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission on day 7 after dosing, and another patient (25%) in the 18 mg group had MADRS clinical response on day 7 after dosing. The mean MADRS change from baseline on day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

At day 7, seven of eight patients (87.5%) achieved MADRS remission, achieving the primary endpoint (p<0.0001).The mean MADRS change from baseline at day 7 was 24.4 (76%).

No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or measures of cognitive function in Part A or Part B.

The results are summarized in the table below.

Table 1-A Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing regimen (IDR). Item scores represent the sum of individual patient scores for all patients (n=8) in the IDR group. Assessment 2 hours (MADRS) or 3 hours (BPRS) after administration of the last dose.

Table 1-B Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients (n=8) in the IDR group. Assessment on Day 1.

Scale items Scale Baseline IDR Day 7 Improvement on Day 7 Percent Improvement Reduced sleep MADRS 25 9 16 64.00% Difficulty concentrating MADRS 30 9 twenty one 70.00% Laziness MADRS 27 3 twenty four 88.89% Loss of sensation MADRS 36 6 30 83.33% Inner tension MADRS 26 12 14 53.85% Pessimistic thoughts MADRS 28 3 25 89.29% Suicidal thoughts MADRS 11 3 8 72.73% Guilt BPRS 34 10 twenty four 70.59% nervous BPRS 16 10 6 37.50% anxiety BPRS 37 17 20 54.05% Emotional withdrawal BPRS 13 8 5 38.46% Emotional blunting BPRS 15 8 7 46.67%

Table 1-C Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment on Day 7.

Table 2-A Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment 2 hours (MADRS) or 3 hours (BPRS) after dose administration.

Table 2-B Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 1.

Table 2-C Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 7.

Example 6-5-Pharmacokinetic Evaluation of MeO-DMT and Toxoplasmamine

To study the pharmacokinetic properties of 5-MeO-DMT, three groups of 8 subjects were divided. A single dose of 6 mg, 12 mg or 18 mg 5-MeO-DMT was administered to the subjects via inhalation. Blood samples were obtained at 1; 2; 4; 7; 10; 15: 20: 30; 45 minutes and 1; 1.5; 2; 3; 4 hours after administration, respectively.

5-MeO-DMT concentrations were determined using LC-MS/MS. PK parameters were generated by algebraic analysis of concentration versus time plots for each individual. Analysis was performed using Phoenix WinNonlin 6.3 software.

The median Cmax values obtained for the three groups were 11.85 ng/ml (6 mg group), 22.90 ng/ml (12 mg group), and 38.45 ng/ml (18 mg group), respectively.

Table 3 below shows the median percentage of plasma concentration relative to Cmax determined at the indicated time points.

Pharmacokinetic measurements were also performed for a dosing regimen that relied on up-titration, and substantially similar results were obtained.

The blood concentration of the 5-MeO-DMT metabolite bufotoxin was also determined. Only in a few samples were the concentrations above the lower limit of quantification (LLOQ) (25 pg/ml). From 15 minutes onwards, the bufotoxin concentrations were always below the LLOQ.

Essentially similar observations were made when subjects who received an up-titration regimen were included.

Example 7-5-Toxicology Testing of MeO-DMT

5-MeO-DMT did not induce mutations in four histidine-requiring bacterial strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101). These conditions included treatment at concentrations up to 5000 μg/plate (the maximum concentration recommended according to current regulatory guidelines) in the absence and presence of a rat liver metabolic activation system (S-9).

Example 8 - Clinical Trial of Administering 5-MeO-DMT to Patients with Postpartum Depression via Inhalation

This single-arm, open-label clinical trial will involve 15 adult female patients clinically diagnosed with postpartum depression (PPD).

Patients received a single-day individualized 5-MeO-DMT dosing regimen via vaporized inhalation.

More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.

1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

2. The second dose (12 mg) will be administered only in the following cases:

a. Peak experience (total score ≥ 75) not achieved after 6 mg dose, and

b. According to the researchers, the 6 mg dose was safe and well tolerated.

c. Any psychoactive effects (PsE) from the previous dose have resolved, and

d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

3. Similarly, the third dose (18 mg) will only be administered if:

a. Peak experience not achieved after 12 mg dose (total score ≥ 75), and

b. According to the researchers, the 12 mg dose was safe and well tolerated, and

c. Any PsE from the previous dose has resolved, and

d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

Patients will be assessed for peak psychedelic experience (based on a patient-rated visual analog scale, or PE scale), sedation, and other endpoints after dosing. Follow-up visits are planned on days 1 and 7 after dosing.

All patients considered for participation in a clinical trial must meet the following criteria:

1. Be female and be between 18 and 45 years old (inclusive) at the time of screening.

2. Body mass index (BMI) at screening is within the range of 18.5 to 35 kg/ ^m2 (inclusive).

3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or registered psychologist:

a. A diagnosis of major depressive disorder without psychotic features confirmed by the Mini-International Neuropsychiatric Interview (MINI), with perinatal onset no earlier than pregnancy and no later than the first 4 weeks postpartum.

b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at screening and on Day 0 before dosing.

6. Patients must stop breastfeeding at the time of screening; or if they are still breastfeeding or actively breastfeeding at the time of screening, they must agree to temporarily stop breastfeeding from before receiving the study drug on Day 0 to 24 hours after the last dose, and express and discard all breast milk within these 24 hours as needed, but they need to express/discard breast milk 2.5 hours after the last dose and 24 hours after the last dose before they can resume breastfeeding.

4. Must agree to complete abstinence (completely avoid heterosexual intercourse) or use highly effective (failure rate <1%), medically approved contraceptive methods 30 days before administration and 90 days after 5-MeO-DMT administration. Patients must have negative pregnancy test results at screening and the day before the test (Day 1).

5. Willing to postpone the start of other antidepressant or antianxiety medications until after the end of the trial on Day 7, and agree to keep any psychological therapy unchanged during the trial.

Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder, manic or hypomanic episodes, psychotic disorders, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient unsuitable for the trial.

2. One or more first- or second-degree relatives currently or previously diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

3. The patient is at significant risk of suicide based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as judged by the trial psychiatrist or registered psychologist.

4. Taking antidepressants within 14 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

5. Any other drug with monoamine oxidase inhibitor (MAOI) activity has been taken within 14 days or 5 half-lives (whichever is longer) before administration.

6. Previous serious adverse reactions to hallucinogenic or psychedelic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) based on the investigator's judgment.

7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

8. Any current or past clinically significant illness that, in the investigator's judgment, makes the patient unsuitable for participation in the trial (e.g., severe infection, lung disease, uncontrolled hypertension, new-onset gestational hypertension disorder during pregnancy or postpartum (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia), uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness).

9. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

11. Patient has a positive pregnancy test at Screening or the day before testing (Day 1), is pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT administration.

12. The patient has a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

The primary objective of the trial was to determine the onset and 7-day durability of the antidepressant effect of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult female patients with PPD.

Secondary objectives were to determine the antidepressant effects, anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE) of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult women with PPD; and effects on cognitive outcomes.

The exploratory objective was to determine the amounts of 5-MeO-DMT and metabolites, bufotoxin, and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine (metabolite identification screening could be performed as needed) following single-day administration of a single individualized IDR (6 mg, 12 mg, and 18 mg 5-MeO-DMT) to adult female PPD patients as measured by LC/MS/MS.

The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

Secondary endpoints included evaluation of the antidepressant effect of 5-MeO-DMT by:

The antidepressant effects of 5-MeO-DMT were evaluated by:

o Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

ο Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

o Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

ο Change from baseline in Clinical Global Impression-Severity (CGI-S) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

Effects on maternal behavior, as assessed by change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores;

Exposure to 5-MeO-DMT and bufotoxin in breast milk obtained on the day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, on the evening of Day 0, and on Days 1 and 7;

5-MeO-DMT and bufotoxin exposure in blood obtained one day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, and on Days 1 and 7;

To evaluate the safety and tolerability of 5-MeO-DMT by:

ο Reporting of treatment-emergent adverse events (TEAEs);

ο Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, peak flow spirometry;

o Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA/S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

o Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

o Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

ο Change from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

ο Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

ο PsE assessment using the Peak Experience (PE) scale to assess the achievement of PE (PE scale total score ≥ 75);

ο Challenging Experience Questionnaire (CEQ);

οMystical Experience Questionnaire (MEQ-30);

Duration of PsE was defined as the time from the time of study drug administration to the time when PsE had resolved (investigator-rated and patient-rated), which was completed within 30 to 60 minutes after each dose;

Currently, one patient diagnosed with postpartum depression by a psychiatrist has been recruited to participate in the clinical trial. The diagnosis of major depressive disorder without psychotic features was confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2) with perinatal onset no earlier than during pregnancy and no later than the first 4 weeks postpartum. The patient was diagnosed with postpartum depression after the birth of her third child. The patient completed all scheduled clinic days. The inhalation procedure was adequately performed by the patient and well tolerated, with no adverse events related to the inhalation.

result

No other noteworthy changes in vital parameters occurred, except for a transient, clinically insignificant increase in heart rate and blood pressure shortly after 5-MeO-DMT administration. ECG (3 hours after administration) and safety laboratory analysis (7 days), CADSS (3 hours, 1 day, and 7 days) were unremarkable. The few adverse events reported (left abdominal cramping pain and headache, both on day 0) were mild, transient, and resolved spontaneously by the end of the study.

Regarding the intensity of the psychedelic experience, the PES score achieved upon exposure to the nominal dose of 6 mg was recorded to be 17.3. This score indicated that a subsequent higher dose of 12 mg would need to be continued as per the design of the individualized dosing regimen. The PES score achieved at this dose was 85.7 and ≥75, indicating that the patient had a peak psychedelic experience and completed the IDR.

It is noteworthy that patients reported significant improvements in their depressive symptoms, as assessed by MADRS at the earliest assessment time point (2 hours) after drug administration, and the effect was maintained over time (Table 4). Patients also met the criteria for MADRS response (at least 50% improvement compared to baseline) and MADRS remission (MADRS total score equal to or less than 10).

Table 4-MADRS/BPRS scoring table

Significant improvements were noted in several MADRS items in particular. The individual items are summarized in Table 4. Patients' baseline scores for some items reflected the absence of symptoms (decreased appetite, difficulty concentrating, suicidal thoughts), while scores for items reflecting severe symptoms (e.g., decreased sleep, inner tension) improved significantly.

Likewise, several BPRS items improved, including somatic problems, anxiety, emotional withdrawal, guilt, and tension.

Summary and Conclusion

A. An individualized dosing regimen of 6 mg 5-MeO-DMT followed by 12 mg 5-MeO-DMT via inhalation was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

B. Rapid clinical response within 2 hours after 5-MeO-DMT administration. This rapid onset of action is not common and has not been seen in traditional antidepressant classes, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSR1), serotonin-norepinephrine reuptake inhibitors (SNR1), etc., which usually take 4 to 6 weeks to show effects.

C. According to the IDR, the patient experienced clinical remission within 2 hours of 5-MeO-DMT administration. This is superior to any approved treatment for postpartum depression as well as all previously tested psychedelics.

D. Although 5-MeO-DMT was only administered once and was no longer effectively present in the body within this time frame (see pharmacokinetic data above), a significant clinical response persisted over the 7-day follow-up period. This observation supports the superior clinical profile of 5-MeO-DMT and allows for convenient dosing intervals.

E. In addition to the antidepressant effects, endpoints assessing other symptoms (such as somatic problems, emotional withdrawal, anxiety, guilt, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

The salient aspects demonstrate that 5-MeO-DMT, when used according to the dosing regimen of the present invention, has significantly improved efficacy compared to approved pharmacotherapy for postpartum depression and all previously tested psychedelics.

Example 9 - Clinical Trial of Administering 5-MeO-DMT to Bipolar II Patients via Inhalation

This single-arm, open-label clinical trial will involve 15 adult patients with bipolar II disorder and a current major depressive episode.

Patients currently taking antidepressant medications need to stop taking them or taper off the medication over time.

Patients received a single-day individualized 5-MeO-DMT dosing regimen via vaporized inhalation.

More specifically, patients will receive up to three doses of 5-MeO-DMT on the administration day (Day 0): 6 mg, 12 mg, and 18 mg.

1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

2. The second dose (12 mg) will be administered only in the following cases:

a. Peak experience not achieved after 6 mg dose (PES total score ≥ 75), and

b. The 6 mg dose was safe and well tolerated.

3. Similarly, the third dose (18 mg) will only be administered if:

a. Peak experience not achieved after 12 mg dose (PES total score ≥ 75), and

b. The 12 mg dose was safe and well tolerated.

The patients’ peak psychedelic experience will be assessed based on the patient-rated PES described above, sedation after dosing, and other endpoints. Follow-up visits are planned on days 1 and 7 after dosing.

Patient selection was based on the following key inclusion criteria:

1. Understand the nature of the clinical trial and provide signed and dated written informed consent in accordance with local regulations before any trial-related procedures are carried out.

2. Male or female, aged between 18 and 64 years old (inclusive) at the time of screening.

3. Meets trial criteria for bipolar disorder type II and is experiencing a major depressive episode as assessed by the trial psychiatrist or registered clinical psychologist:

a. Meet the diagnostic criteria for bipolar II disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and be confirmed to have a current episode of major depressive disorder by the Mini-International Neuropsychiatric Interview (MINI);

b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 24 at screening and before the first dose on Day 0;

4. The total score of the Young's Mania Rating Scale (YMRS) is less than or equal to 8 at screening and before the first dose on day 0;

5. Agree to keep any psychotherapy unchanged and not start any new psychoactive medications during the trial.

6. Female patients must be surgically sterilized (hysterectomy, tubal ligation or bilateral oophorectomy (6 months before screening)), or be postmenopausal and have been amenorrheic or completely abstinent (completely avoiding heterosexual intercourse) for the past 2 years, or use a medically approved highly effective (failure rate <1%) contraceptive method 30 days before and 90 days after 5-MeO-DMT administration, including but not limited to bilateral tubal ligation/blockage, hormonal contraceptives that suppress ovulation, intrauterine devices (including hormone-releasing intrauterine devices/systems), and must have a negative serum pregnancy test at screening and a negative urine pregnancy test on the day before the test (day -1).

7. Male patients must use preventive contraception (i.e., use of condoms containing spermicide or abstinence) and must not donate sperm within 30 days of 5-MeO-DMT administration.

Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder type I, manic episode, psychotic disorder, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient unsuitable for the trial.

2. One or more first- or second-degree relatives currently or previously diagnosed with a psychotic disorder, bipolar disorder type I, or MDD with psychotic features.

3. Significant suicide risk, defined as: (a) suicidal ideation as described in C-SSRS Item 4 or 5 within the past year, during the screening period, or at baseline; or (b) suicidal behavior within the past year; or (c) clinical assessment of significant suicide risk during the clinical interview; or (d) non-suicidal self-injurious behavior within the past year.

4. Taking antidepressants within 7 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

5. Taking drugs with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) before administration.

6. Received mood stabilizer therapy (e.g., lamotrigine, valproate, atypical antipsychotics) within 14 days (28 days for lithium) or 5 half-lives (whichever is longer) prior to dosing, or received mood stabilizer therapy at screening, or is expected to require mood stabilizer therapy during the study (based on the investigator's judgment).

7. Previous serious adverse reactions to hallucinogens or psychedelic drugs, as determined by the investigator.

8. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

9. Suffering from any current or past clinically significant illness (e.g., severe infection, severe lung disease, uncontrolled hypertension, uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness) that may interfere with the interpretation of the trial results, pose a risk to the patient's health, or make the patient unsuitable for participation in the trial according to the investigator's judgment.

10. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

11. Clinically significant abnormalities in physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

12. Female patients with a positive pregnancy test at screening or the day before testing (Day 1), are pregnant or breastfeeding, or plan to become pregnant during the course of the trial and up to 30 days after 5-MeO-DMT administration.

13. Patients with DSM-5, alcohol or substance use disorder (excluding tobacco or caffeine use disorder) within 6 months prior to screening.

The primary objective of the trial was to determine the onset and duration of antidepressant effects of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in patients with bipolar II disorder and a current major depressive episode. Secondary objectives were to determine the effects of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) on depressive symptoms and global clinical status in patients with bipolar II disorder and a current major depressive episode; safety and tolerability; the effects on the intensity and duration of psychoactive effects (PsE); the effects on sleep quality; and the effects on cognitive outcomes.

The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

Secondary endpoints include:

The antidepressant effects of 5-MeO-DMT administered via inhalation were evaluated by:

o Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

ο Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

o Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

ο Change from baseline in CGI-S assessed 2 hours after the final study drug dose on Day 0 and on Days 1 and 7;

ο Change from baseline in BDRS at Day 1 and Day 7

To evaluate the safety and tolerability of 5-MeO-DMT administered by inhalation by:

ο Reporting of treatment-emergent adverse events (TEAEs);

ο Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and spirometry assessments;

o Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA/S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

ο The incidence of adverse events (AEs) of mania or hypomania (assessed using DSM-5 criteria for mania/hypomania);

ο Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

o Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

ο Assess patient readiness for discharge on discharge day 0 using the Clinical Assessment of Discharge Readiness (CADR);

o Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

ο C-SSRS classification based on the Columbia Suicide Assessment Classification Algorithm (C-CASA).

Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

ο PsE assessment using the Peak Experience (PE) Scale (PES) to assess the achievement of PE (PES total score ≥ 75);

ο Challenging Experience Questionnaire (CEQ);

οMystical Experience Questionnaire (MEQ-30).

Duration of PsE was defined as the time from study drug administration to when PsE had resolved, which was completed within 30 to 60 minutes after each dose;

Effect on sleep quality, as assessed by the change in the Pittsburgh Sleep Quality Index (PSQI) from the day before testing (Day 1) to Day 1 and to Day 7.

Effects on cognitive outcomes, as assessed by change from the day before testing (Day 1) to discharge Day 0, to Day 1, and to Day 7:

ο Rapid visual processing (RVP) test;

οVerbal recognition memory (VRM) test;

ο Spatial working memory (SWM) test;

οDigit Symbol Substitution Test (DSST).

Claims (283)

1. 5-Methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of a patient diagnosed with bipolar disorder.
2. 2. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 1, wherein the patient is diagnosed with bipolar disorder type II.
3. 3. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 1, wherein the patient is diagnosed with bipolar disorder type I.
4. 4. A 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 3, wherein the patient suffers from a current major depressive episode.
5. 5. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 4, wherein the patient has a montgomery-asberg depression rating scale (MADRS) total score equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.
6. 6. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 4 or claim 5, wherein the patient's Bipolar Depression Rating Scale (BDRS) total score is equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.
7. 7. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 6, wherein the patient is not substantially improved after at least two substantial courses of treatment.
8. 8. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 6, wherein the patient is not substantially improved after at least two substantial courses of treatment, wherein at least one of the two courses is drug therapy.
9. 9. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 6, wherein the patient is not substantially improved after at least two substantial drug courses.
10. 10. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 9, wherein the patient has a total score of less than or equal to 8 on the yankee mania scale (YMRS).
11. 11. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered at a dose or dose regimen that causes the patient to experience a peak fantasy experience.
12. 12. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 11, wherein a dose of about 4mg to about 20mg of 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.
13. 13. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 11, wherein a dose of about 6mg or about 12mg or about 18mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.
14. 14. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 12, wherein the 5-MeO-DMT or salt thereof is administered at a first dose upon first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a higher dose than the previous administration unless the patient experiences a peak illusive experience.
15. 15. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-14, wherein the 5-MeO-DMT is administered at a dose of about 2mg to about 8mg at a first administration, then increases to a dose of about 8mg to about 14mg at a second administration unless the patient has experienced a peak vague experience, then increases to a dose of about 14mg to about 20mg at a third administration unless the patient has experienced a peak vague experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.
16. 16. The 5-MeO-DMT for use of claim 15, or a pharmaceutically acceptable salt thereof, wherein the first dose of 5-MeO-DMT is about 6mg, the second dose of 5-MeO-DMT is about 12mg, and the third dose of 5-MeO-DMT is about 18mg; or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.
17. 17. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 14 to 16, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.
18. 18. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 11 to 17, wherein the occurrence of peak fantasy experiences is identified by reaching at least 60% of the highest possible score in each of the four sub-scales (mystery, positive emotion, override time and space and self-evident) of the 30 project revised mystery experience questionnaire (MEQ 30), or by reaching at least 60% of the highest possible score of the marine-like borderless (OBN) dimension in the state of consciousness change (ASC) questionnaire, or by reaching at least 75 Peak Experience Scale (PES) total score.
19. 19. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 18, wherein the occurrence of peak illusion experiences is identified by reaching a Peak Experience Scale (PES) score of at least 75.
20. 20. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of any one of the preceding claims, wherein the 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is administered via inhalation, or by nasal, buccal, or sublingual administration.
21. 21. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 20, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas; (b) Aerosol particles of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of from about 0.5mg/l to about 18mg/l, such as to about 12.5 mg/l.
22. 22. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 21, wherein the aerosol is generated by: a) Exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer to produce aerosol particles.
23. 23. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 20 to 22, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled by a single breath.
24. 24. The 5-MeO-DMT for use according to claims 20 to 23, wherein the 5-MeO-DMT is used in the form of a free base.
25. 25. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 24, wherein the clinical response reflected as a decrease in clinical overall impression-severity (CGI-S) score occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
26. 26. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 25, wherein a clinical response is observed at day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in a decrease in the clinical overall impression-severity (CGI-S) score.
27. 27. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 26, wherein the clinical response is continued until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in a decrease in the clinical global impression-severity (CGI-S) score.
28. 28. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 27, wherein the clinical response is continued until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in a decrease in the clinical global impression-severity (CGI-S) score.
29. 29. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 28, wherein the clinical response is continued until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in a decrease in the clinical global impression-severity (CGI-S) score.
30. 30. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 29, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in an improvement in BDRS, MADRS or HAM-D scores of at least 50% compared to the corresponding scores prior to treatment.
31. 31. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 30, wherein relief from symptoms of depression occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, said relief being reflected in a BDRS score equal to or less than 10; the MADRS score is equal to or less than 10, or the HAM-D score is equal to or less than 7.
32. 32. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 31, wherein a clinical response is observed at day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in an improvement of the BDRS, MADRS or HAM-D score by at least 50% compared to the corresponding score before treatment.
33. 33. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 32, wherein relief of symptoms of depression is observed at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, said relief being reflected in a BDRS score equal to or less than 10; the MADRS score is equal to or less than 10, or the HAM-D score is equal to or less than 7.
34. 34. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 33, wherein the clinical response, reflected in at least a 50% improvement in BDRS, MADRS or HAM-D scores compared to the corresponding scores before treatment, continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
35. 35. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 34, wherein a clinical response is present at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in an improvement in BDRS, MADRS or HAM-D score of at least 75% compared to the corresponding score prior to treatment.
36. 36. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 35, wherein the patient has a relief in symptoms of depression on day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, said relief being reflected in a BDRS score equal to or less than 10; the MADRS score is equal to or less than 10, or the HAM-D score is equal to or less than 7.
37. 37. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 36, wherein the clinical response, reflected in at least a 50% improvement in BDRS, MADRS or HAM-D scores compared to the corresponding scores before treatment, continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
38. 38. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 37, wherein a clinical response is present at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in an improvement in BDRS, MADRS or HAM-D score of at least 75% compared to the corresponding score prior to treatment.
39. 39. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 38, wherein the patient has a relief on day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, in depression symptoms reflected in a BDRS score equal to or less than 10; the MADRS score is equal to or less than 10, or the HAM-D score is equal to or less than 7.
40. 40. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 39, wherein the clinical response, reflected in at least a 50% improvement in BDRS, MADRS or HAM-D scores compared to the corresponding scores prior to treatment, continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
41. 41. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 40, wherein a clinical response is present at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being reflected in an improvement in BDRS, MADRS or HAM-D score of at least 75% compared to the corresponding score prior to treatment.
42. 42. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1 to 41, wherein the patient has a relief on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, in depression symptoms reflected in a BDRS score of 10 or less; the MADRS score is equal to or less than 10, or the HAM-D score is equal to or less than 7.
43. 43. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 1 to 42, wherein the patient is not experiencing mania or hypomania caused by treatment.
44. 44. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 43, wherein the patient has a total Young Mania Rating Scale (YMRS) score of less than or equal to 15, preferably less than or equal to 12, as assessed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
45. 45. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 44, wherein the patient has a total Young Mania Rating Scale (YMRS) score of less than or equal to 15, preferably less than or equal to 12, as assessed on day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
46. 46. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 45, wherein the patient has a total Young Mania Rating Scale (YMRS) score of less than or equal to 15, preferably less than or equal to 12, as assessed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
47. 47. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 46, wherein the patient has a total Young Mania Rating Scale (YMRS) score of less than or equal to 15, preferably less than or equal to 12, as assessed on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
48. 48. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 47, wherein the patient has a total Young Mania Rating Scale (YMRS) score of less than or equal to 15, preferably less than or equal to 12, as assessed at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
49. 49. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 1 to 48, wherein the treatment results in an improvement in at least one of sleep disorders, bradykinesia, negative thinking, anxiety, cognitive dysfunction, and social/emotional withdrawal or deficits.
50. 50. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 49, wherein the patient suffers from a sleep disorder and the treatment reduces or eliminates the sleep disorder.
51. 51. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, wherein the patient suffers from insomnia and the treatment reduces or eliminates insomnia.
52. 52. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 50, wherein the patient suffers from excessive sleep and the treatment reduces or eliminates excessive sleep.
53. 53. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 50 to 52, wherein the reduction or elimination of sleep disturbance is reflected at least in an improvement in the score of sleep disturbance as item BDRS at day 1, e.g., 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
54. 54. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 50 to 53, wherein the reduction or elimination of sleep disturbance is reflected at least in an improvement in the score of item BDRS of sleep disturbance on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
55. 55. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 50-54, wherein the reduction or elimination of sleep disturbance is reflected at least in an improvement in the score of item BDRS of sleep disturbance at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
56. 56. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 50 to 55, wherein the reduction or elimination of sleep disturbance is reflected at least in an improvement in the score of item BDRS of sleep disturbance at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
57. 57. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, wherein the reduction or elimination of sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the BDRS item sleep disturbance.
58. 58. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 57, wherein the reduction or elimination of sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the sleep disorder under item BDRS.
59. 59. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 57, wherein the reduction or elimination of sleep disorder continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the sleep disorder under item BDRS.
60. 60. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 57, wherein the reduction or elimination of sleep disorder continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the sleep disorder of item BDRS.
61. 61. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder is reflected at least in an improvement in the score of reduced sleep for the MADRS project at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
62. 62. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50 or 61, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder is reflected at least in an improvement in the score of reduced sleep of the MADRS project at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
63. 63. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, 61, or 62, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder is reflected at least in an improvement in the score of the reduction in MADRS project sleep at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
64. 64. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50 or 61-63, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder is reflected at least in an improvement in the score of the reduction in MADRS project sleep at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
65. 65. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score for reduced sleep for the MADRS program.
66. 66. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 65, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score for reduced sleep for the MADRS project.
67. 67. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 65, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score for reduced sleep for the MADRS project.
68. 68. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 65, wherein the sleep disorder is reduced sleep and the reduction or elimination of sleep disorder continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score for reduced sleep for the MADRS project.
69. 69. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, wherein the patient suffers from a sleep disorder and the improvement in sleep disorder is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
70. 70. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50 or 69, wherein the patient suffers from a sleep disorder and the improvement in sleep disorder is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
71. 71. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, 69, or 70, wherein the patient suffers from a sleep disorder and the improvement in sleep disorder is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
72. 72. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 50 or 69-71, wherein the patient suffers from a sleep disorder and the improvement in sleep disorder is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
73. 73. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-49, wherein the patient suffers from a sleep disorder and the improvement in sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
74. 74. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 73, wherein the improvement in sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
75. 75. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 73, wherein the improvement in sleep disorder persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
76. 76. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 73, wherein the improvement in sleep disorder persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
77. 77. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-49, wherein the patient suffers from a sleep disorder and the reduction or elimination of a sleep disorder is reflected in an improvement in the overall score of, e.g., about 24 hours Pittsburgh Sleep Quality Index (PSQI) at day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the point in time when the acute illusive experience subsides after the last dose to the point in time of evaluation.
78. 78. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-49 or 77, wherein the patient suffers from a sleep disorder and the reduction or elimination of a sleep disorder is reflected in an improvement in the overall score of the Pittsburgh Sleep Quality Index (PSQI) on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the point in time when the last dose of acute illusive experience resolved to the point in time of evaluation.
79. 79. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-49, 77, or 78, wherein the patient suffers from a sleep disorder and the reduction or elimination of a sleep disorder is reflected in an improvement in the overall score of the Pittsburgh Sleep Quality Index (PSQI) on day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the point in time when the last dose of acute illusive experience subsides to the point in time of evaluation.
80. 80. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-49 or 77-79, wherein the patient suffers from a sleep disorder and the reduction or elimination of a sleep disorder is reflected in an improvement in the overall score of the Pittsburgh Sleep Quality Index (PSQI) at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the point in time when the last dose of acute illusive experience subsides to the point in time of evaluation.
81. 81. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 50, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected as an improvement in the overall score of the Pittsburgh Sleep Quality Index (PSQI), wherein the recall period spans from the point in time of the resolution of the acute illusive experience after the last administration to the point in time of evaluation.
82. 82. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected as an improvement in the overall score of the Pittsburgh Sleep Quality Index (PSQI), wherein the recall period spans from the point in time of the resolution of the acute illusive experience after the last administration to the point in time of evaluation.
83. 83. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of sleep disorder persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected as an improvement in the overall score of the Pittsburgh Sleep Quality Index (PSQI), wherein the recall period spans from the point in time of the resolution of the acute illusive experience after the last administration to the point in time of evaluation.
84. 84. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of sleep disorder persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected as an improvement in the overall score of the Pittsburgh Sleep Quality Index (PSQI), wherein the recall period spans from the point in time of the resolution of the acute illusive experience after the last administration to the point in time of evaluation.
85. 85. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-84, wherein the patient suffers from mental retardation and the treatment reduces or eliminates the mental retardation.
86. 86. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 85, wherein the treatment improves or eliminates reduced effort and activity and/or reduced motivation.
87. 87. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 85 or 86, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of the decrease in energy and activity and/or motivation of item BDRS, about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
88. 88. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 85-87, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of reduced energy and activity and/or reduced motivation, e.g., item BDRS, at day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
89. 89. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 85-88, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of the BDRS items of reduced energy and activity and/or reduced motivation at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
90. 90. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 85-89, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of the BDRS items of reduced energy and activity and/or reduced motivation at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
91. 91. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 85-90, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of item BDRS of reduced energy and activity and/or reduced motivation at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
92. 92. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 85 or 86, wherein the reduction or elimination of mental retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the project BDRS for reduced energy and activity and/or reduced motivation.
93. 93. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 92, wherein the reduction or elimination of mental retardation continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the project BDRS for reduced energy and activity and/or reduced motivation.
94. 94. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 92, wherein the reduction or elimination of mental retardation continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the project BDRS for reduced energy and activity and/or reduced motivation.
95. 95. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 92, wherein the reduction or elimination of mental retardation continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the project BDRS for reduced energy and activity and/or reduced motivation.
96. 96. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 85, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of MADRS project lazy about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
97. 97. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 85 or 96, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of MADRS project lazy at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
98. 98. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 85, 96, or 97, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of MADRS project lazy at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
99. 99. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 85 or 96-98, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of MADRS project lazy at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
100. 100. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 85 or 96-99, wherein the reduction or elimination of mental retardation is reflected at least in an improvement in the score of MADRS project lazy at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
101. 101. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 85, wherein the reduction or elimination of mental retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of MADRS project lazy.
102. 102. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 101, wherein the reduction or elimination of mental retardation continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for MADRS project lazy.
103. 103. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 101, wherein the reduction or elimination of mental retardation continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for MADRS project lazy.
104. 104. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 101, wherein the reduction or elimination of mental retardation continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of MADRS project lazy.
105. 105. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 85, wherein the patient suffers from bradykinesia and improvement in bradykinesia is reflected in a decrease in clinical overall impression-severity (CGI-S) score of about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
106. 106. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 85 or 105, wherein the patient suffers from bradykinesia and improvement in bradykinesia is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
107. 107. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 85, 105 or 106, wherein the patient suffers from bradykinesia and improvement in bradykinesia is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
108. 108. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 85 or 105-107, wherein the patient suffers from bradykinesia and improvement in bradykinesia is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
109. 109. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 85 or 105-108, wherein the patient suffers from bradykinesia and improvement in bradykinesia is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
110. 110. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-84, wherein the patient suffers from bradykinesia and improvement in bradykinesia occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
111. 111. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 110, wherein the improvement in mental retardation continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
112. 112. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 110, wherein the improvement in mental retardation continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
113. 113. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 110, wherein the improvement in mental retardation continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
114. 114. The 5-MeO-DMT for use of claims 1 to 113, or a pharmaceutically acceptable salt thereof, wherein the patient suffers from negative thoughts and the treatment reduces or eliminates the negative thoughts.
115. 115. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114, wherein the treatment reduces or eliminates a feeling of invalidity, helplessness, and hopelessness and/or guilt.
116. 116. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114 or 115, wherein said reduction or elimination of negative cravings is reflected at least in an improvement in the score of items BDRS as a worthless, helplessness and hopeless and/or guilt about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
117. 117. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 114-116, wherein said reduction or elimination of negative cravings is reflected at least in an improvement in the score of, e.g., about 24 hours BDRS item worthless, helplessness and hopeless and/or guilt at day 1 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
118. 118. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 114-117, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of item BDRS as of no value, no assistance and no hope and/or guilt at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
119. 119. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 114-118, wherein said reduction or elimination of negative cravings is reflected at least in an improvement in the score of item BDRS as of no value, no assistance and no hope and/or guilt at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
120. 120. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 114-119, wherein said reduction or elimination of negative cravings is reflected at least in an improvement in the score of item BDRS as of no value, no assistance and no hope and/or guilt at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
121. 121. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114 or 115, wherein the reduction or elimination of negative cravings occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the items BDRS as worthless, helplessness and hopeless and/or guilt.
122. 122. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 121, wherein the reduction or elimination of negative thinking continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of items BDRS of worthiness, helplessness and hopelessness and/or guilt.
123. 123. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 121, wherein the reduction or elimination of negative thinking continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of items BDRS of worthiness, helplessness, and hopelessness and/or guilt.
124. 124. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 121, wherein the reduction or elimination of negative thinking continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of items BDRS of worthiness, helplessness and hopelessness and/or guilt.
125. 125. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114 or 115, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the pessimistic ideas of the MADRS project about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
126. 126. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 114, 115, or 125, wherein said reduction or elimination of negative cravings is reflected at least in an improvement in the score of pessimistic ideas of the MADRS project at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
127. 127. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114, 115, 125, or 126, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the pessimistic idea of the MADRS project on day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
128. 128. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 114, 115, or 125-127, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the pessimistic idea of the MADRS project at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
129. 129. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 114, 115, or 125-128, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the pessimistic idea of the MADRS project at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
130. 130. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114 or 115, wherein the reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of pessimistic thoughts for the MADRS project.
131. 131. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 130, wherein the reduction or elimination of negative thinking continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of pessimistic ideas of the MADRS project.
132. 132. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 130, wherein the reduction or elimination of negative thinking continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of pessimistic ideas of the MADRS project.
133. 133. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 130, wherein the reduction or elimination of negative thinking continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of pessimistic ideas of the MADRS project.
134. 134. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 114 or 115, wherein said reduction or elimination of negative cravings is reflected at least in an improvement in the score of the BPRS project guilt about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
135. 135. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114, 115, or 134, wherein said reduction or elimination of negative cravings is reflected at least in an improvement in the score of guilt sensation in the BPRS project at about 24 hours, at day 1, after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
136. 136. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114, 115, 134, or 135, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the guilt sensation of the BPRS project at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
137. 137. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 114, 115, or 134-136, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the guilt sensation of the BPRS project at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
138. 138. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 114, 115, or 134-137, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of BPRS project guilt feel at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
139. 139. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 114 or 115, wherein said reduction or elimination of negative cravings occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, said reduction or elimination reflecting an improvement in the score of guilt sensation in the BPRS project.
140. 140. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 139, wherein said reduction or elimination of negative thinking continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, said reduction or elimination reflecting an improvement in the score of guilt feel in the BPRS project.
141. 141. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 139, wherein said reduction or elimination of negative thinking continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, said reduction or elimination reflecting an improvement in the score of guilt feel in the BPRS project.
142. 142. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 139, wherein said reduction or elimination of negative thinking continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, said reduction or elimination reflecting an improvement in the score of guilt feel in the BPRS project.
143. 143. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 114 or 115, wherein the patient suffers from negative thoughts and improvement in negative thoughts is reflected in a decrease in clinical overall impression-severity (CGI-S) score of about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
144. 144. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 114, 115 or 143, wherein the patient suffers from negative thoughts and improvement in negative thoughts is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
145. 145. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 114, 115, 143, or 144, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
146. 146. The 5-MeO-DMT for use of claims 114, 115 or 143 to 145, or a pharmaceutically acceptable salt thereof, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
147. 147. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 114, 115, or 143-146, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
148. 148. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-113, wherein the patient suffers from negative thoughts and improvement in negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
149. 149. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 148, wherein the improvement in negative thinking continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
150. 150. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 148, wherein the improvement in negative thinking continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
151. 151. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 148, wherein the improvement in negative thinking continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
152. 152. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-151, wherein the patient suffers from anxiety and the treatment reduces or eliminates the anxiety.
153. 153. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of item BDRS of anxiety 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
154. 154. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152 or 153, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of item BDRS of anxiety at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
155. 155. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 152-154, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of item BDRS at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
156. 156. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 152-155, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of item BDRS at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
157. 157. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 152-156, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of item BDRS at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
158. 158. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152, wherein the reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of item BDRS anxiety.
159. 159. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 158, wherein the reduction or elimination of anxiety continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of anxiety of item BDRS.
160. 160. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 158, wherein the reduction or elimination of anxiety continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of anxiety of item BDRS.
161. 161. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 158, wherein the reduction or elimination of anxiety continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of anxiety of item BDRS.
162. 162. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of BPRS project anxiety about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
163. 163. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152 or 162, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS project anxiety at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
164. 164. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 152, 162, or 163, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of BPRS project anxiety at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
165. 165. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 152 or 162-164, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS project anxiety at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
166. 166. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 152 or 162-165, wherein the reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS project anxiety at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
167. 167. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152, wherein the reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of anxiety for the BPRS project.
168. 168. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 167, wherein the reduction or elimination of anxiety continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of anxiety for the BPRS project.
169. 169. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 167, wherein the reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of anxiety for the BPRS project.
170. 170. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 167, wherein the reduction or elimination of anxiety continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of anxiety for the BPRS project.
171. 171. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in clinical global impression-severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
172. 172. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152 or 171, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
173. 173. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 152, 171, or 172, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
174. 174. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 152 or 171-173, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
175. 175. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 152 or 171-174, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
176. 176. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-151, wherein the patient suffers from anxiety and improvement in anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
177. 177. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 176, wherein the improvement in anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
178. 178. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 176, wherein the improvement in anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
179. 179. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 176, wherein the improvement in anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
180. 180. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-179, wherein the patient suffers from cognitive dysfunction and the treatment reduces or eliminates the cognitive dysfunction.
181. 181. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the concentration and memory impairment of item BDRS about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
182. 182. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180 or 181, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of impaired concentration and memory at day 1, e.g., item BDRS, e.g., 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
183. 183. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 180-182, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of BDRS items concentration and memory impairment at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
184. 184. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 180-183, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of BDRS items concentration and memory impairment at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
185. 185. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 180-184, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of BDRS items concentration and memory impairment at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
186. 186. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180, wherein the reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for the BDRS project concentration and memory impairment.
187. 187. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 186, wherein the reduction or elimination of cognitive dysfunction continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for the concentration and memory impairment of item BDRS.
188. 188. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 186, wherein the reduction or elimination of cognitive dysfunction continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for the concentration and memory impairment of item BDRS.
189. 189. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 186, wherein the reduction or elimination of cognitive dysfunction continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for the concentration and memory impairment of item BDRS.
190. 190. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the difficulty focused score of the MADRS project about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
191. 191. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180 or 190, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score that is refractory to MADRS program, e.g., for about 24 hours, on day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
192. 192. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180, 190, or 191, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score that MADRS project is refractory to attention at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
193. 193. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 180 or 190-192, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score that MADRS project is refractory to attention at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
194. 194. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 180 or 190-193, wherein the reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score that MADRS project is refractory to attention at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
195. 195. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180, wherein the reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in scores that are refractory to MADRS programs.
196. 196. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 195, wherein the reduction or elimination of cognitive dysfunction continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of difficulty concentrating the MADRS program.
197. 197. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 195, wherein the reduction or elimination of cognitive dysfunction continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of difficulty concentrating the MADRS program.
198. 198. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 195, wherein the reduction or elimination of cognitive dysfunction continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of difficulty concentrating for the MADRS program.
199. 199. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in clinical overall impression-severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
200. 200. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180 or 199, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
201. 201. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 180, 199, or 200, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
202. 202. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 180 or 199-201, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
203. 203. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 180 or 199-202, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 28 following the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
204. 204. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-179, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
205. 205. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 204, wherein the improvement in cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which improvement is reflected in a decrease in clinical global impression-severity (CGI-S) score.
206. 206. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 204, wherein the improvement in cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical global impression-severity (CGI-S) score.
207. 207. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 204, wherein the improvement in cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which improvement is reflected in a decrease in clinical global impression-severity (CGI-S) score.
208. 208. The 5-MeO-DMT for use of claims 1 to 207, or a pharmaceutically acceptable salt thereof, wherein the patient suffers from social/emotional withdrawal or distraction, and the treatment reduces or eliminates the social/emotional withdrawal or distraction.
209. 209. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208, wherein the treatment reduces or eliminates at least one of a lack of hedonia, emotional withdrawal, and frigidity.
210. 210. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208 or 209, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the lack of hedonia, emotional withdrawal, and/or emotional frigidity of item BDRS about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
211. 211. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 208-210, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of e.g., about 24 hours BDRS item lack of hedonia, emotional withdrawal, and/or emotional frigidity at day 1 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
212. 212. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 208-211, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the BDRS items lack of hedonia, emotional withdrawal, and/or emotional frigidity at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
213. 213. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 208-212, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the BDRS items lack of hedonia, emotional withdrawal, and/or emotional frigidity at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
214. 214. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 208-213, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the BDRS items lack of hedonia, emotional withdrawal, and/or emotional frigidity at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
215. 215. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208 or 209, wherein the reduction or elimination of social/emotional withdrawal or distraction occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the BDRS items for lack of hedonia, emotional withdrawal, and/or emotional frigidity.
216. 216. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 215, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the reduction or elimination reflecting an improvement in the score of the items BDRS for lack of hedonia, emotional withdrawal, and/or emotional frigidity.
217. 217. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 215, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the reduction or elimination reflecting an improvement in the score of the items BDRS for lack of hedonia, emotional withdrawal, and/or emotional frigidity.
218. 218. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 215, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the reduction or elimination reflecting an improvement in the score of the items BDRS for lack of hedonia, emotional withdrawal, and/or emotional frigidity.
219. 219. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in score of MADRS project sensory deficit about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
220. 220. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 208, 209, or 219, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of MADRS project sensory deficit at day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, e.g., about 24 hours.
221. 221. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208, 209, 219, or 220, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of MADRS project sensory deficit at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
222. 222. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 208, 209, or 219 to 221, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of MADRS project sensory deficit at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
223. 223. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 208, 209, or 219-222, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of MADRS project sensory deficit at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
224. 224. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 208 or 209, wherein the reduction or elimination of social/emotional withdrawal or distraction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination reflecting an improvement in the score for sensory deficit in the MADRS project.
225. 225. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 224, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination reflecting an improvement in the score for MADRS project sensory deficit.
226. 226. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 224, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the reduction or elimination reflecting an improvement in the score for MADRS project sensory deficit.
227. 227. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 224, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination reflecting an improvement in the score of MADRS project sensory deficit.
228. 228. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208 or 209, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the emotional withdrawal of the BPRS project about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
229. 229. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208, 209, or 228, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the emotional withdrawal of the BPRS item at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
230. 230. The 5-MeO-DMT for use of claim 208, 209, 228, or 229, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the emotional withdrawal of the BPRS project at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
231. 231. The 5-MeO-DMT for use of claims 208, 209, or 228-230, or a pharmaceutically acceptable salt thereof, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the emotional withdrawal of the BPRS project at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
232. 232. The 5-MeO-DMT for use of claims 208, 209, or 228-231, or a pharmaceutically acceptable salt thereof, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the emotional withdrawal of the BPRS project at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
233. 233. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208 or 209, wherein the reduction or elimination of social/emotional withdrawal or distraction occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of emotional withdrawal for the BPRS project.
234. 234. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 233, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for emotional withdrawal of the BPRS project.
235. 235. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 233, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for emotional withdrawal of the BPRS project.
236. 236. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 233, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score for emotional withdrawal of the BPRS project.
237. 237. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208 or 209, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of BPRS project emotional dullness about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
238. 238. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 208, 209, or 237, wherein the reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of the emotional dullness of the BPRS project at day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, e.g., about 24 hours.
239. 239. The 5-MeO-DMT for use of claim 208, 209, 237, or 238, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of BPRS project emotional retardation at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
240. 240. The 5-MeO-DMT for use of claims 208, 209, or 237 to 239, or a pharmaceutically acceptable salt thereof, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of BPRS project emotional retardation at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
241. 241. The 5-MeO-DMT for use of claims 208, 209, or 237 to 240, wherein said reduction or elimination of social/emotional withdrawal or distraction is reflected at least in an improvement in the score of BPRS project emotional retardation at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
242. 242. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208 or 209, wherein the reduction or elimination of social/emotional withdrawal or distraction occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the emotional dullness of the BPRS project.
243. 243. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 242, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the emotional retardation of the BPRS project.
244. 244. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 242, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the emotional retardation of the BPRS project.
245. 245. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 242, wherein the reduction or elimination of social/emotional withdrawal or distraction continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the emotional retardation of the BPRS project.
246. 246. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208 or 209, wherein the patient suffers from social/emotional withdrawal or distraction and an improvement in social/emotional withdrawal or distraction is reflected in a decrease in clinical overall impression-severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
247. 247. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 208, 209, or 246, wherein the patient suffers from social/emotional withdrawal or distraction and improvement in social/emotional withdrawal or distraction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
248. 248. The 5-MeO-DMT for use of claim 208, 209, 246, or 247, or a pharmaceutically acceptable salt thereof, wherein the patient suffers from social/emotional withdrawal or distraction and improvement in social/emotional withdrawal or distraction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
249. 249. The 5-MeO-DMT for use of claims 208, 209, or 246 to 248, or a pharmaceutically acceptable salt thereof, wherein the patient suffers from social/emotional withdrawal or distraction and improvement in social/emotional withdrawal or distraction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
250. 250. The 5-MeO-DMT for use of claims 208, 209, or 246-249, or a pharmaceutically acceptable salt thereof, wherein the patient suffers from social/emotional withdrawal or distraction and improvement in social/emotional withdrawal or distraction is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
251. 251. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-207, wherein the patient suffers from social/emotional withdrawal or distraction and improvement in social/emotional withdrawal or distraction occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
252. 252. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 251, wherein the improvement in social/emotional withdrawal or distraction continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
253. 253. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 251, wherein the improvement in social/emotional withdrawal or distraction continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
254. 254. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 251, wherein the improvement in social/emotional withdrawal or distraction continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
255. 255. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-254, wherein the treatment reduces or eliminates suicidal ideation.
256. 256. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255, wherein the reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of item BDRS of suicidal ideation about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
257. 257. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255 or 256, wherein the reduction or elimination of suicide is reflected at least in an improvement in the score of suicide at day 1, e.g., about 24 hours BDRS, after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
258. 258. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 255-257, wherein the reduction or elimination of suicide is reflected at least in an improvement in the score of item BDRS of suicide at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
259. 259. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 255-258, wherein the reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of item BDRS of suicidal ideation at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
260. 260. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 255-259, wherein the reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of item BDRS of suicidal ideation at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
261. 261. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255, wherein the reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the suicide of item BDRS.
262. 262. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 261, wherein the reduction or elimination of suicidal ideation continues until at least 6 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the suicide of item BDRS.
263. 263. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 261, wherein the reduction or elimination of suicidal ideation continues until at least 14 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the suicide of item BDRS.
264. 264. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 261, wherein the reduction or elimination of suicidal ideation continues until at least 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination is reflected in an improvement in the score of the suicide of item BDRS.
265. 265. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255, wherein the reduction or elimination of suicide ideas is reflected at least in an improvement in the score of the MADRS project suicide ideas about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
266. 266. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255 or 265, wherein the reduction or elimination of suicide concept is reflected at least in an improvement in the score of the MADRS project suicide idea on day 1 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for example, about 24 hours.
267. 267. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255, 265, or 266, wherein the reduction or elimination of suicide concept is reflected at least in an improvement in the score of the MADRS project suicide idea at day 7 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
268. 268. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 255 or 265-267, wherein the reduction or elimination of suicide concept is reflected at least in an improvement in the score of the MADRS project suicide idea at day 14 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
269. 269. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255 or 265-268, wherein the reduction or elimination of suicide ideas is reflected at least in an improvement in the score of the MADRS project suicide ideas at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
270. 270. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255, wherein the reduction or elimination of suicide concept occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of the suicide concept of the MADRS project.
271. 271. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 270, wherein the reduction or elimination of suicidal ideation continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of the MADRS project suicidal ideation.
272. 272. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 270, wherein the reduction or elimination of suicidal ideation continues until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of the MADRS project suicidal ideation.
273. 273. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 270, wherein the reduction or elimination of suicidal ideation continues until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduction or elimination reflects an improvement in the score of the MADRS project suicidal ideation.
274. 274. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 255, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in clinical overall impression-severity (CGI-S) score of about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
275. 275. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 255 or 274, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
276. 276. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 255, 274, or 275, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 7 following the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
277. 277. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 255 or 274-276, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
278. 278. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 255 or 274-277, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in clinical overall impression-severity (CGI-S) score at day 28 following the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
279. 279. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-254, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in clinical overall impression-severity (CGI-S) score.
280. 280. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 279, wherein the improvement in suicidal ideation is continued until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which improvement is reflected in a decrease in clinical overall impression-severity (CGI-S) score.
281. 281. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 279, wherein the improvement in suicidal ideation is continued until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which improvement is reflected in a decrease in clinical overall impression-severity (CGI-S) score.
282. 282. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 279, wherein the improvement in suicidal ideation is continued until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which improvement is reflected in a decrease in clinical overall impression-severity (CGI-S) score.
283. 283. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claims 1-282, wherein the treatment reduces or eliminates at least one of psychotic symptoms, irritability, instability, increased motor drive, increased speech, agitation.